Compound having cyclic structure

ABSTRACT

An object of the present invention is to provide a compound having an anti-inflammatory activity or a pharmacologically acceptable salt thereof. 
     The solution of the present invention is a compound of general formula (1) or a pharmacologically acceptable salt thereof. 
     
       
         
         
             
             
         
       
     
     wherein the symbols in the formula are defined below:
 
A: e.g., Benzene, E: e.g., —CH 2 —, G: e.g., a 5-membered aromatic heterocyclic ring, X: e.g., cyclohexane, J: e.g., a 5-membered aromatic heterocyclic ring, Y: e.g., a phenyl group, R 1 , R 2 , R 3 : e.g., a halogen atom, R 4 : e.g., a C1-C6 alkyl group, R 5 : e.g., a hydrogen atom, R 6a , R 6b , R 6c , R 6d : e.g., a hydrogen atom, R 7 : e.g., a hydrogen atom, R 8 : e.g., a hydrogen atom, n 1 , n 2 , n 3 : e.g., 1.

TECHNICAL FIELD

The present invention relates to a compound having a specific chemicalstructure having a peripheral and/or central anti-inflammatory activityor a pharmacologically acceptable salt thereof, and a production methodthereof, or the like. The present invention also relates to a mechanismof action, a pharmaceutical composition, a production method of thepharmaceutical composition, a method of prevention and/or treatment andthe like, regarding the compound or a pharmacologically acceptable saltthereof.

BACKGROUND ART

Patent Reference 1 reports the following 5-membered aromaticheterocyclic compounds, but the anti-inflammatory activity of thesecompounds is not known.

Along with advances in research, relationships between psychiatric orneurodegenerative diseases and inflammation have been reported in recentyears (Non patent References 1 and 2).

It has been reported that stress increases production of inflammatorycytokines from microglia and that patients with mental diseases (such asdepression and schizophrenia) have high levels of blood cytokines (TNFαor the like), suggesting the involvement of brain inflammation inpsychiatric diseases. Furthermore, in neurodegenerative diseases such asAlzheimer's disease, it has been suggested that proteins, which areconsidered to be the cause of the disease, provoke brain inflammationthrough microglia activation.

CITATION LIST Patent Reference

-   Patent Reference 1: WO2010/001946

Non Patent References

-   Non patent Reference 1: Kadota Akira, Hypothesis of    neuroinflammation of mental illness, Psychiatria et Neurologia    Japonica, (2012), 114(2): 124-133-   Non patent Reference 2: Suzumura Akio, Neurodegenerative disease,    Neuroinflammation and microglia, Clinical Neurology, (2014), 54:    1119-1121

SUMMARY OF INVENTION Technical Problem

The present invention provides a compound and a pharmacologicallyacceptable salt thereof or the like, having a specific chemicalstructure having an anti-inflammatory activity, which are useful as anactive ingredient for preventing and/or treating an inflammatorydisease. The present invention also provides a novel production methodand an intermediate therefor. Since the compound and a pharmacologicallyacceptable salt thereof of the present invention have differentproperties from known anti-inflammatory drugs in various aspects, theyare considered to be useful as a novel medicine.

The compound and a pharmacologically acceptable salt thereof of thepresent invention have excellent properties in terms ofanti-inflammatory activity, bioavailability, solubility, cell membranepermeability, oral absorbability, blood concentration, metabolicstability, tissue migration, in vitro activity, in vivo activity, exvivo activity, rapid onset of drug efficacy, sustained drug efficacy,physical stability, drug interaction, safety (such as cardiotoxicity orhepatotoxicity) and the like, and have been found to be useful as amedicinal drug.

Solution to Problem

The present inventors conducted intensive studies for developing acompound which is useful as an active ingredient for preventing and/ortreating an inflammatory disease, a pharmacologically acceptable saltthereof or the like. As a result, they found the compound and apharmacologically acceptable salt thereof or the like of the presentinvention. More specifically, the present invention is as describedbelow.

A compound of general formula (1) or a pharmacologically acceptable saltthereof:

wherein the symbols in the formula are defined below:A: a 5- to 6-membered aromatic heterocycle, a 4- to 7-membered saturatedheterocycle, benzene, cyclohexane or a ring having the followingstructure, wherein each of the rings has at least one bond;

E: —CH₂—, —O—, or a single bond;G: a 5-membered aromatic heterocycle, wherein the ring has at least twobonds; if the ring has a nitrogen atom(s), at least one of the nitrogenatom(s) is next to an atom that is attached to a right-hand portion,wherein the right-hand portion refers to the following portion in thecompound of general formula (1):

wherein the symbols indicating the respective substituents are the sameas defined above;

X: any ring selected from the following rings, wherein the any ringincludes a ring condensed with additional atoms to form a bicyclic ring,and wherein the any ring has at least two bonds:

wherein

A⁴, A⁵: each independently, —CH═ or —N═,

A⁶, A⁷: each independently, —CH₂—, —O—, or —NH—,

m¹, m², m=: each independently, 0, 1, 2, or 3;

J: a 5-membered aromatic heterocycle wherein J is optionally condensedwith X to have a bicyclic structure, or a 5-membered unsaturatedheterocycle, wherein the ring has at least two bonds;

Y:

an amino group optionally substituted with 1-2 groups independentlyselected from Substituent group Y¹,

a phenyl group optionally substituted with 1-3 groups independentlyselected from Substituent group Y¹,

a C3-C8 cycloalkyl group optionally substituted with 1-3 groupsindependently selected from Substituent group Y¹, wherein the C3-C8cycloalkyl group optionally has the following bridged structures:

a C3-C8 cycloalkenyl group optionally substituted with 1-3 groupsindependently selected from Substituent group Y¹,

a 4- to 7-membered saturated heterocyclic group optionally substitutedwith 1-3 groups independently selected from Substituent group Y¹,

a 4- to 7-membered unsaturated heterocyclic group optionally substitutedwith 1-3 groups independently selected from Substituent group Y¹, or

a group formed by attachment to R⁷, optionally substituted with 1-3groups independently selected from Substituent group Y¹, selected fromthe following:

Substituent group Y¹:

a hydroxyl group,

an amino group optionally substituted with 1-2 groups independentlyselected from Substituent group Y²,

a cyano group,

a halogen atom;

a C1-C6 alkyl group optionally substituted with 1-3 groups independentlyselected from Substituent group Y²,

a C1-C6 alkoxy group optionally substituted with 1-3 groupsindependently selected from Substituent group Y²,

a 4- to 7-membered saturated heterocyclic group optionally substitutedwith 1-3 groups independently selected from Substituent group Y², and

any group optionally substituted with 1-3 groups independently selectedfrom Substituent group Y², selected from the following:

Substituent group Y²:

a hydroxyl group,

a halogen atom,

a C1-C6 alkyl group optionally substituted with 1-3 groups independentlyselected from Substituent group Y³,

a C1-C6 alkoxy group optionally substituted with 1-3 groupsindependently selected from Substituent group Y³,

an amino group optionally substituted with 1-2 groups independentlyselected from Substituent group Y³,

a 4- to 7-membered saturated heterocyclic group optionally substitutedwith 1-3 groups independently selected from Substituent group Y³, and

any group optionally substituted with 1-3 groups independently selectedfrom Substituent group Y³, selected from the following:

Substituent group Y³:

a hydroxyl group,

a halogen atom,

a cyano group,

a C1-C6 alkyl group,

a C1-C6 alkoxy group,

a C1-C6 alkyl group optionally substituted with 1-3 groups independentlyselected from Substituent group Y⁴,

a C1-C6 alkoxy group optionally substituted with 1-3 groupsindependently selected from Substituent group Y⁴, and

any group optionally substituted with 1-3 groups independently selectedfrom Substituent group Y⁴, selected from the following:

Substituent group Y⁴:

a fluorine atom.

R¹, R², R³: each independently, a hydrogen atom, a carboxyl group, acyano group, a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group,a C3-C8 cycloalkyl group, a C3-C8 cycloalkoxy group, a hydroxy C1-C6alkyl group, a halo C1-C6 alkyl group, a halo C1-C6 alkoxy group, aC1-C6 alkoxycarbonyl group, a C1-C6 alkyl C3-C8 cycloalkyl group, aC3-C8 cycloalkyl C1-C6 alkoxy group, a 4- to 7-membered unsaturatedheterocyclic group, a C1-C6 alkyl 4- to 7-membered unsaturatedheterocyclic group, a di(C1-C6 alkyl)amino 4- to 7-membered unsaturatedheterocyclic group, a 4- to 7-membered unsaturated heterocyclic carbonylgroup, or a C3-C8 cycloalkylcarbonyl group.

R⁴: a hydrogen atom, a C1-C6 alkyl group, a halo C1-C6 alkyl group, or agroup formed by attachment to R^(6c) or R^(6d), selected from thefollowing:

wherein m⁴ is 0, 1, or 2, and R^(m4) is a hydrogen atom or a methylgroup,

R⁵: a hydrogen atom, a halogen atom, or a C1-C6 alkyl group,R^(6a), R^(6b), R^(6c), R^(6d): each independently, a hydrogen atom or aC1-C6 alkyl group,R⁷: a single bond, a hydrogen atom, or a methyl group,R⁸: a hydrogen atom or a methyl group, andn¹, n², n³: each independently, 0, 1, or 2.

[2]

A compound or a pharmacologically acceptable salt thereof according to[1], wherein A is a 6-membered aromatic heterocycle or benzene, each ofwhich has at least one bond.

[3]

A compound or a pharmacologically acceptable salt thereof according to[1], wherein A is pyridine or benzene, each of which has at least onebond.

[4]

A compound or a pharmacologically acceptable salt thereof according toany one of [1] to [3], wherein each of R^(6a), R^(6b), R^(6c) is ahydrogen atom, R^(6d) is a hydrogen atom or a methyl group, n¹ is 0, n²is 1, and E is —O—.

[5]

A compound or a pharmacologically acceptable salt thereof according toany one of [1] to [4], wherein G is the following:

[6]

A compound or a pharmacologically acceptable salt thereof according toany one of [1] to [5], wherein X is benzene, pyridine or cyclohexane,each of which has at least two bonds, and R⁵ is the same as definedabove.

[7]

A compound or a pharmacologically acceptable salt thereof according toany one of [1] to [6], wherein J is a ring selected from the followingring group:

and R⁷ is a hydrogen atom, or a single bond.

[8]

A compound or a pharmacologically acceptable salt thereof according toany one of [1] to [7], wherein R¹, R², and R³ are, each independently, ahydrogen atom, a carboxyl group, a cyano group, a fluorine atom, achlorine atom, a methyl group, an isopropyl group, a t-butyl group, atrifluoromethyl group, a trifluoromethoxy group, a cyclopropylmethoxygroup, a 1,1-difluoro-2-methylpropyl group, a1,1-difluoro-2,2-dimethylpropyl group, a 1-methyl-1-cyclobutyl group, amethoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonylgroup, a 1-hydroxy-1-methylethyl group, an azetidine-1-carbonyl group, a3-methyloxetan-3-yl group, a 4,5-dihydrooxazol-2-yl group, or acyclopropylcarbonyl group.

[9]

A compound of general formula (1′) or a pharmacologically acceptablesalt thereof:

wherein the symbols in the formula are defined below:

R¹: a hydrogen atom, a carboxyl group, a cyano group, a fluorine atom, achlorine atom, a methyl group, an isopropyl group, a t-butyl group, atrifluoromethyl group, a trifluoromethoxy group, a cyclopropylmethoxygroup, a 1,1-difluoro-2-methylpropyl group, a1,1-difluoro-2,2-dimethylpropyl group, a 1-methyl-1-cyclobutyl group, amethoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonylgroup, a 1-hydroxy-1-methylethyl group, an azetidine-1-carbonyl group, a3-methyloxetan-3-yl group, a 4,5-dihydrooxazol-2-yl group, or acyclopropylcarbonyl group;R^(6d): a hydrogen atom or a methyl group;

A¹: ═N—, or ═CH—;

X: benzene, pyridine or cyclohexane, each of which has two bonds;J: any ring selected from the following ring group:

Y:

an amino group optionally substituted with 1-2 groups independentlyselected from Substituent group Y¹,

a phenyl group optionally substituted with 1-3 groups independentlyselected from Substituent group Y¹,

any group optionally substituted with 1-3 groups independently selectedfrom Substituent group Y¹, selected from the following:

a cyclobutyl group, a cyclopentyl group, a cyclohexyl group,

a cyclohexenyl group optionally substituted with 1-3 groupsindependently selected from Substituent group Y¹,

any group optionally substituted with 1-3 groups independently selectedfrom Substituent group Y¹, selected from the following:

a piperidinyl group, an azetidinyl group, a tetrahydropyranyl group, amorpholinyl group, or

a tetrahydropyridinyl group optionally substituted with 1-3 groupsindependently selected from Substituent group Y¹;

Substituent group Y:

a hydroxyl group,

an amino group optionally substituted with 1-2 groups independentlyselected from Substituent group Y²,

a cyano group,

a fluorine atom,

a methyl group, an ethyl group or an isopropyl group optionallysubstituted with 1-3 groups independently selected from Substituentgroup Y²,

a methoxy group optionally substituted with 1-3 groups independentlyselected from Substituent group Y²,

an azetidinyl group, a pyrrolidinyl group or a morpholinyl groupoptionally substituted with 1-3 groups independently selected fromSubstituent group Y², and

any group optionally substituted with 1-3 groups independently selectedfrom Substituent group Y², selected from the following:

Substituent group Y²:

a hydroxyl group,

a fluorine atom,

a methyl group optionally substituted with 1-3 groups independentlyselected from Substituent group Y³,

a methoxy group optionally substituted with 1-3 groups independentlyselected from Substituent group Y³,

an amino group optionally substituted with 1-2 groups independentlyselected from Substituent group Y³,

an azetidinyl group, a pyrrolidinyl group or a morpholinyl groupoptionally substituted with 1-3 groups independently selected fromSubstituent group Y³, and

any group optionally substituted with 1-3 groups independently selectedfrom Substituent group Y³, selected from the following:

Substituent group Y³:

a hydroxyl group,

a fluorine atom,

a cyano group,

a methyl group optionally substituted with 1-3 groups independentlyselected from Substituent group Y⁴, and

a methoxy group optionally substituted with 1-3 groups independentlyselected from Substituent group Y⁴;

Substituent group Y⁴:

a fluorine atom.

[10]

A compound or a pharmacologically acceptable salt thereof selected fromthe following group:

-   4-Fluoro-1-methyl-4-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine,-   4-{4-[(1R)-1-(Azetidin-1-yl)ethyl]phenyl}-1-[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazole,-   (3R,6S)—N,N-Dimethyl-6-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}tetrahydro-2H-pyran-3-amine,-   4-Fluoro-1-methyl-4-{1-[(3R,6S)-6-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)tetrahydro-2H-pyran-3-yl]-1H-1,2,3-triazol-4-yl}piperidine,-   3-{trans-4-[4-(4-Fluoro-1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}-8-[3-(trifluoromethyl)phenoxy]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine,-   1,5-Anhydro-6-azetidin-1-yl-2,3,4,6-tetradeoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-1-yl}-D-erythro-hexitol,-   2-({5-[trans-4-(1-{trans-4-[3-(Fluoromethyl)azetidin-1-yl]cyclohexyl}-1H-1,2,3-triazol-4-yl)cyclohexyl]-4-methyl-4H-1,2,4-triazol-3-yl}methoxy)-4-(trifluoromethyl)pyridine,-   3-(trans-4-{1-[trans-4-(Azetidin-1-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole,-   4-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]morpholine,-   6-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-2-oxa-6-azaspiro[3.3]heptane,-   6-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-1-oxa-6-azaspiro[3.3]heptane,-   2-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-6-oxa-2-azaspiro[3.4]octane,-   {1-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-1H-pyrazol-1-yl)cyclohexyl]azetidine-3,3-diyl}dimethanol,-   Methyl    3-{[4-methyl-5-(trans-4-{1-[trans-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methoxy}benzoate,    and-   8-Methyl-3-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene.

[11]

-   4-Fluoro-1-methyl-4-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine.

[12]

-   (3R,6S)—N,N-Dimethyl-6-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}tetrahydro-2H-pyran-3-amine.

[13]

-   2-({5-[trans-4-(1-{trans-4-[3-(Fluoromethyl)azetidin-1-yl]cyclohexyl}-1H-1,2,3-triazol-4-yl)cyclohexyl]-4-methyl-4H-1,2,4-triazol-3-yl}methoxy)-4-(trifluoromethyl)pyridine.

[14]

-   6-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-2-oxa-6-azaspiro[3.3]heptane.

[15]

-   6-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-1-oxa-6-azaspiro[3.3]heptane.

[16]

-   2-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-6-oxa-2-azaspiro[3.4]octane.

[17]

-   Methyl    3-{[4-methyl-5-(trans-4-{1-[trans-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methoxy}benzoate.

[18]

A compound or a pharmacologically acceptable salt thereof according toany one of [1] to [17], for increasing IL10.

[19]

A pharmaceutical composition comprising a compound or apharmacologically acceptable salt thereof according to any one of [1] to[18] as an active ingredient.

[20]

A pharmaceutical composition according to [19], for preventing and/ortreating an inflammatory disease.

[21]

A pharmaceutical composition according to [20], wherein the inflammatorydisease is a peripheral inflammatory disease.

[22]

A pharmaceutical composition according to [20], wherein the inflammatorydisease is a central inflammatory disease.

[23]

A pharmaceutical composition according to [21], wherein the peripheralinflammatory disease is a disease selected from the group consisting ofrheumatoid arthritis, systemic lupus erythematosus, scleroderma,bronchial asthma, asthmatic bronchitis, diffuse interstitial pneumonia,chronic obstructive pulmonary disease, ulcerative colitis, Crohn'sdisease, celiac disease, anal fistula, radiation enterocolitis, acutehepatitis, chronic hepatitis, fulminant hepatitis, autoimmune hepatitis,primary biliary cirrhosis, primary sclerosing cholangitis, alcoholichepatitis, non-alcoholic steatohepatitis, cirrhosis, peripheralneuritis, ankylosing spondylitis, eczema (acute, subacute, chronic),contact dermatitis, sunlight (ultraviolet light) dermatitis, radiationdermatitis, atopic dermatitis, seborrheic dermatitis, psoriasisvulgaris, arthropathic psoriasis, psoriatic erythroderma, pustularpsoriasis, lichen planus, erythema, rosacea, urticaria, alopecia areata,pemphigus, erythroderma, acne vulgaris, pressure sore, wound, burn,conjunctivitis, keratitis, scleritis, acute/chronic otitis media,perennial allergic rhinitis, hay fever, sinusitis, laryngitis,esophagitis, refractory stomatitis, glossitis, acute/chronic salivarygland inflammation, angular cheilitis, cheilitis, Behcet's disease,multiple sclerosis, Type I diabetes, Type II diabetes, atherosclerosis,pancreatitis and chronic heart failure.

[24]

A pharmaceutical composition according to [21], wherein the peripheralinflammatory disease is a disease selected from the group consisting ofrheumatoid arthritis, systemic lupus erythematosus, bronchial asthma,ulcerative colitis, Crohn's disease, celiac disease, anal fistula,radiation enterocolitis, acute hepatitis, autoimmune hepatitis, primarybiliary cirrhosis, primary sclerosing cholangitis, alcoholic hepatitis,nonalcoholic steatohepatitis, ankylosing spondylitis, contactdermatitis, sunlight (ultraviolet light) dermatitis, atopic dermatitis,seborrheic dermatitis, psoriasis vulgaris, arthropathic psoriasis,psoriatic erythroderma, pustular psoriasis, lichen planus, erythema,rosacea, alopecia areata, pemphigus, erythroderma, acne vulgaris,pressure sore, wound, burn, sinusitis, laryngitis, esophagitis,refractory stomatitis, glossitis, acute/chronic salivary glandinflammation, angular cheilitis, cheilitis and Behcet's disease.

[25]

A pharmaceutical composition according to [21], wherein the peripheralinflammatory disease is a disease selected from the group consisting ofrheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis,Crohn's disease, celiac disease, anal fistula, radiation enterocolitis,autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis,ankylosing spondylitis, wound, refractory stomatitis, glossitis andBehcet's disease.

[26]

A pharmaceutical composition according to [22], wherein the centralinflammatory disease is a disease selected from the group consisting ofAlzheimer's disease, Parkinson's disease, dementia with Lewy bodies,multiple system atrophy, Pick's disease, progressive supranuclear palsy,basal ganglia degeneration, frontotemporal lobar degeneration,Huntington's disease, amyotrophic lateral sclerosis, bulbar spinalmuscular atrophy, spinal muscular atrophy, spinocerebellar degeneration,multiple sclerosis, Creutzfeldt-Jakob disease, lethal familial insomnia,Gerstmann-Streisler-Shinker syndrome, Down syndrome, Niemann-Pickdisease, cerebral amyloid angiopathy, HIV encephalopathy, influenzaencephalopathy, hepatic encephalopathy, progressive multifocalleukoencephalopathy, anti-NMDA receptor antibody encephalitis,cerebrovascular disorder, traumatic brain injury, spinal cord injury,hypoxia encephalopathy, epilepsy, optic neuritis, congenital metabolicbrain disease, Wernicke encephalopathy, autism spectrum disorder,attention deficit/hyperactivity disorder, tic disorder, schizophrenia,bipolar disorder, major depressive disorder (treatment-resistantdepression, postpartum depression), persistent depressive disorder(dysthymia), menstruation pre-discomfort mood disorder, anxietydisorder, localized phobia, panic disorder, obsessive compulsivedisorder, trauma and stress factor related disorder, eating disorder,circadian rhythm sleep/wake disorder, narcolepsy, substance-relateddisorder (alcohol dependence, drug dependence), impulse controldisorder, delirium, personality disorder, and Rett syndrome.

[27]

A pharmaceutical composition according to [22], wherein the centralinflammatory disease is a disease selected from the group consisting ofAlzheimer's disease, Parkinson's disease, dementia with Lewy bodies,multiple system atrophy, Pick's disease, progressive supranuclear palsy,basal ganglia degeneration, frontotemporal lobar degeneration,Huntington's disease, amyotrophic lateral sclerosis, bulbar spinalmuscular atrophy, spinal muscular atrophy, spinocerebellar degeneration,multiple sclerosis, Creutzfeldt-Jakob disease, schizophrenia, bipolardisorder, major depressive disorder (treatment-resistant depression,postpartum depression), persistent depressive disorder (dysthymia),menstruation pre-discomfort mood disorder, anxiety disorder, localizedphobia, panic disorder, obsessive compulsive disorder, trauma and stressfactor related disorder, eating disorder, circadian rhythm sleep/wakedisorder, narcolepsy, substance-related disorder (alcohol dependence,drug dependence), impulse control disorder, delirium, personalitydisorder, and Rett syndrome.

[28]

A pharmaceutical composition according to [22], wherein the centralinflammatory disease is a disease selected from the group consisting ofschizophrenia, bipolar disorder, major depressive disorder(treatment-resistant depression, postpartum depression), persistentdepressive disorder (dysthymia), menstruation pre-discomfort mooddisorder, anxiety disorder, localized phobia, panic disorder, andobsessive compulsive disorder.

[29]

A compound or a pharmacologically acceptable salt thereof according toany one of [1] to [17], for use in the treatment of an inflammatorydisease.

[30]

A method of preventing and/or treating an inflammatory disease,comprising administering an effective amount of a pharmaceuticalcomposition according to [19].

[31]

A crystal of a compound according to [11] (Example 4), having peaks atdiffraction angles (2θ(°)) of about 3.9, 4.1, 8.34, 12.6, 16.2, 18.4,19.5 and 22.3 by powder X-ray diffraction.

[32]

A crystal of a compound according to [11] (Example 4), having an X-raydiffraction pattern shown in FIG. 1.

[33]

A crystal of a compound according to [12] (Example 8), having peaks atdiffraction angles (2θ(°)) of about 3.8, 16.4, 18.0, 18.6, 19.8, 21.2and 22.7 by powder X-ray diffraction.

[34]

A crystal of a compound according to [12] (Example 8), having an X-raydiffraction pattern shown in FIG. 2.

[35]

A crystal of a compound according to [13] (Example 20), having peaks atdiffraction angles (2θ(°)) of about 13.5, 15.7, 17.2, 17.8, 18.2, 19.2,20.4, 20.8, 22.0 and 27.2 by powder X-ray diffraction.

[36]

A crystal of a compound according to [13] (Example 20), having an X-raydiffraction pattern shown in FIG. 3.

[37]

A crystal of a compound according to [14] (Example 24), having peaks atdiffraction angles (2θ(°)) of about 3.3, 13.4, 15.5, 16.8, 17.5, 17.9,18.9, 20.4, 21.8 and 26.9 by powder X-ray diffraction.

[38]

A crystal of a compound according to [14] (Example 24), having an X-raydiffraction pattern shown in FIG. 4.

[39]

A crystal of a compound according to [15] (Example 25), having peaks atdiffraction angles (2θ(°)) of about 13.2, 15.8, 16.5, 17.8, 18.1, 20.3,20.8, 21.4 and 27.9 by powder X-ray diffraction.

[40]

A crystal of a compound according to [15] (Example 25), having an X-raydiffraction pattern shown in FIG. 5.

[41]

A crystal of a compound according to [16] (Example 27), having peaks atdiffraction angles (2θ(°)) of about 14.2, 16.8, 17.4, 18.2, 18.6, 19.5,20.0, 20.9, 21.6 and 21.8 by powder X-ray diffraction.

[42]

A crystal of a compound according to [16] (Example 27), having an X-raydiffraction pattern shown in FIG. 6.

[43]

A crystal of a compound according to [17] (Example 31), having peaks atdiffraction angles (2θ(°)) of about 15.4, 17.6, 17.9, 18.4, 18.7, 19.2,20.2, 20.7, 23.0 and 23.8 by powder X-ray diffraction.

[44]

A crystal of a compound according to [17] (Example 31), having an X-raydiffraction pattern shown in FIG. 7.

Advantageous Effects of the Invention

Since the compound and a pharmacologically acceptable salt thereof ofthe present invention, having a specific chemical structure having aperipheral and/or central anti-inflammatory activity, have differentproperties from known anti-inflammatory drugs in various aspects, thecompound or a pharmacologically acceptable salt thereof is considered tobe useful as a novel medicine.

The compounds and pharmacologically acceptable salts thereof of thepresent invention also have excellent properties in terms ofanti-inflammatory activity, bioavailability, in vitro activity, in vivoactivity, rapid onset of drug efficacy, sustained drug efficacy,physical stability, drug interaction, toxicity, and the like, thus theyare useful as a medicinal drug.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of the compound ofExample 4. The vertical axis represents intensity (cps) and thehorizontal axis represents diffraction angle (2θ(°)).

FIG. 2 shows a powder X-ray diffraction pattern of the compound ofExample 8. The vertical axis represents intensity (cps) and thehorizontal axis represents diffraction angle (2θ(°)).

FIG. 3 shows a powder X-ray diffraction pattern of the compound ofExample 20. The vertical axis represents intensity (cps) and thehorizontal axis represents diffraction angle (2θ(°)).

FIG. 4 shows a powder X-ray diffraction pattern of the compound ofExample 24. The vertical axis represents intensity (cps) and thehorizontal axis represents diffraction angle (2θ(°)).

FIG. 5 shows a powder X-ray diffraction pattern of the compound ofExample 25. The vertical axis represents intensity (cps) and thehorizontal axis represents diffraction angle (2θ(°)).

FIG. 6 shows a powder X-ray diffraction pattern of the compound ofExample 27. The vertical axis represents intensity (cps) and thehorizontal axis represents diffraction angle (2θ(°)).

FIG. 7 shows a powder X-ray diffraction pattern of the compound ofExample 31. The vertical axis represents intensity (cps) and thehorizontal axis represents diffraction angle (2θ(°)).

DESCRIPTION OF EMBODIMENTS

Now, the present invention will be more specifically described below.

(Explanation of Substituents and Terms)

An embodiment of the present invention is directed to a compound ofgeneral formula (1) or a pharmacologically acceptable salt thereof.

wherein the symbols indicating the respective substituents are the sameas defined above.

A preferred embodiment of the present invention is directed to acompound of general formula (1′) or a pharmacologically acceptable saltthereof.

wherein the symbols indicating the respective substituents are the sameas defined above.

Suitable combinations of the substituents of the compound of the generalformula (1′) are as follows.

R¹: a hydrogen atom, a carboxyl group, a cyano group, a fluorine atom, achlorine atom, a methyl group, an isopropyl group, a t-butyl group, atrifluoromethyl group, a trifluoromethoxy group, a cyclopropylmethoxygroup, a 1,1-difluoro-2-methylpropyl group, a1,1-difluoro-2,2-dimethylpropyl group, a 1-methyl-1-cyclobutyl group, amethoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonylgroup, a 1-hydroxy-1-methylethyl group, an azetidine-1-carbonyl group, a3-methyloxetan-3-yl group, a 4,5-dihydrooxazol-2-yl group, or acyclopropylcarbonyl group,R^(6d): a hydrogen atom or a methyl group,

A¹: ═N—, or ═CH—,

X: benzene, pyridine or cyclohexane, each of which has two bonds,J: a ring selected from the following ring groups:

Y:

a cyclohexenyl group optionally substituted with 1-3 groupsindependently selected from Substituent group Y¹, Substituent group Y¹:any group optionally substituted with 1-3 groups independently selectedfrom Substituent group Y², selected from the following:

Substituent group Y²:any group selected from the following:

Further preferred embodiments of the present invention are directed to acompound described in the Examples or a pharmacologically acceptablesalt thereof.

Now, substituents and terms used to represent the compounds of thepresent invention or a pharmacologically acceptable salt thereof will bedescribed below.

The term “5- to 6-membered aromatic heterocycle” as used herein is amonocyclic 5- to 6-membered aromatic heterocycle containing 1-4 atomsselected from the group consisting of a nitrogen atom, an oxygen atomand a sulfur atom. Examples of the 5-membered aromatic heterocycleinclude rings as shown below:

Examples of the 6-membered aromatic heterocycle include rings as shownbelow:

The term “5-membered aromatic heterocycle” as used herein is amonocyclic 5-membered aromatic heterocycle containing 1-4 atoms selectedfrom the group consisting of a nitrogen atom, an oxygen atom and asulfur atom, and examples thereof include rings as shown below.

The term “4- to 7-membered saturated heterocycle” as used herein is amonocyclic 4- to 7-membered saturated heterocycle containing 1-3 atomsselected from the group consisting of a nitrogen atom, an oxygen atom,and a sulfur atom, and examples thereof include azetidine, pyrrolidine,imidazolidine, pyrazolidine, oxazolidine, thiazolidine, piperidine,piperazine, hexahydropyrimidine, morpholine, thiomorpholine, oxetane,tetrahydrofuran, tetrahydropyran, dioxane, and preferably includes ringsas shown below.

The term “4- to 7-membered unsaturated heterocycle” as used herein is amonocyclic 4- to 7-membered heterocycle containing 1-3 atoms selectedfrom the group consisting of a nitrogen atom, an oxygen atom and asulfur atom in which the ring is formed from a saturated heterocyclethat is partially oxidized or an aromatic heterocycle that is partiallyreduced, and examples thereof include rings as shown below.

Examples of the term “5-membered unsaturated heterocycle” as used hereininclude pyrroline, imidazoline, pyrazoline, oxazoline, and thiazoline,and preferably include rings as shown below.

The term “C3-C8 cycloalkyl group” as used herein represents a cyclicalkyl group having 3 to 8 carbon atoms, and preferably a cyclopropylgroup, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, acycloheptyl group, or a cyclooctyl group.

The term “C3-C8 cycloalkenyl group” as used herein represents a cyclicalkenyl group having 3 to 8 carbon atoms, and preferably a cyclopropenylgroup, a cyclobutenyl group, a cyclopentenyl group, or a cyclohexenylgroup.

The term “C3-C8 cycloalkoxy group” as used herein is a group, in whichan oxygen atom is bonded to a C3-C8 cycloalkyl group, and preferably acyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, ora cyclohexyloxy group.

The term “C1-C6 alkyl C3-C8 cycloalkyl group” as used herein is a groupin which a C1-C6 alkyl group is bonded to a C3-C8 cycloalkyl group, andpreferably a methylcyclobutanyl group, a methylcyclopentanyl group, amethylcyclohexyl group, an ethylcyclobutanyl group, anethylcyclopentanyl group, and an ethylcyclohexyl group.

The term “C3-C8 cycloalkyl C1-C6 alkoxy group” as used herein is a groupin which a C3-C8 cycloalkyl group is bonded to a C1-C6 alkoxy group, andpreferably a cyclobutanylmethoxy group, a cyclopentanylmethoxy group, acyclohexylmethoxy group, a cyclobutanylethoxy group, acyclopentanylethoxy group, and a cyclohexylethoxy group.

The term “C1-C6 alkyl group” as used herein represents a linear orbranched alkyl group having 1 to 6 carbon atoms, and examples thereofinclude a methyl group, an ethyl group, a 1-propyl group, an isopropylgroup, a 1-butyl group, a 2-butyl group, a 2-methyl-1-propyl group, a2-methyl-2-propyl group, a 1-pentyl group, a 2-pentyl group, a 3-pentylgroup, a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a 1-hexylgroup, a 2-hexyl group, a 3-hexyl group, a 2-methyl-1-pentyl group, a3-methyl-1-pentyl group, a 2-ethyl-1-butyl group, a 2,2-dimethyl-1-butylgroup, and a 2,3-dimethyl-1-butyl group, preferably a methyl group, anethyl group, a 1-propyl group, and an isopropyl group.

The term “di(C1-C6 alkyl) amino group” as used herein represents a groupin which two identical or different C1-C6 alkyl groups are bonded to anamino group, and examples thereof include a dimethylamino group, amethylethylamino group, a methylpropylamino group [such asN-methyl-N-(1-propyl) amino group], a methylbutylamino group [such asN-(1-butyl)-N-methylamino group], a methylpentylamino group, amethylhexylamino group, a diethylamino group, an ethylpropylamino group[such as N-ethyl-N-(1-propyl) amino group], an ethylbutylamino group, adipropylamino group, a propylbutylamino group, a dibutylamino group, adipentylamino group, and a dihexylamino group, preferably adimethylamino group and a diethylamino group.

The term “C1-C6 alkoxy group” as used herein represents a group in whichan oxygen atom is bonded to a C1-C6 alkyl group, and examples thereofinclude a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxygroup, a 1-butoxy group, a 2-butoxy group, a 2-methyl-1-propoxy group, a2-methyl-2-propoxy group, a 1-pentyloxy group, a 2-pentyloxy group, a3-pentyloxy group, a 2-methyl-2-butoxy group a 3-methyl-2-butoxy group,a 1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a2-methyl-1-pentyloxy group, and a 3-methyl-1-pentyloxy group, preferablya methoxy group, an ethoxy group, a 1-propoxy group, and a 2-propoxygroup.

The term “halogen atom” as used herein is a fluorine atom, a chlorineatom, a bromine atom, or an iodine atom, and preferably a fluorine atomor a chlorine atom.

The term “hydroxy C1-C6 alkyl group” as used herein is a group in whicha hydroxyl group is bonded to a C1-C6 alkyl group, and preferably ahydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, ahydroxyisopropyl group, or a hydroxyisobutyl group.

The term “halo C1-C6 alkyl group” as used herein is a group in which aC1-C6 alkyl group is substituted with an appropriate number of halogenatoms, and preferably a difluoromethyl group, a trifluoromethyl group,or a difluoroethyl group.

The term “halo C1-C6 alkoxy group” as used herein is a group in which aC1-C6 alkoxy group is substituted with an appropriate number of halogenatoms, and preferably a difluoromethoxy group, a trifluoromethoxy group,or a difluoroethoxy group.

The term “C1-C6 alkylcarbonyl group” as used herein is a group in whicha C1-C6 alkyl group is bonded to a carbonyl group, and preferably anacetyl group, an ethylcarbonyl group, or a propylcarbonyl group.

The term “C1-C6 alkoxycarbonyl group” as used herein is a group in whicha C1-C6 alkoxy group is bonded to a carbonyl group, and preferably amethoxycarbonyl group, an ethoxycarbonyl group, or a t-butoxycarbonylgroup.

The term “C1-C6 alkyl 4- to 7-membered unsaturated heterocyclic group”as used herein is a group in which a C1-C6 alkyl group is bonded to a 4-to 7-membered unsaturated heterocyclic group.

The term “di(C1-C6 alkyl) amino 4- to 7-membered unsaturatedheterocyclic group” as used herein is a group in which a di(C1-C6 alkyl)amino group is bonded to a 4- to 7-membered unsaturated heterocyclicgroup.

The term “4- to 7-membered unsaturated heterocyclic carbonyl group” asused herein is a group in which a 4- to 7-membered unsaturatedheterocyclic group is bonded to a carbonyl group.

The term “pharmacologically acceptable salt thereof” refers to a saltwhich can be used as a medicinal drug. In the case of a compound havingan acidic group or a basic group, a basic salt or an acid salt can beproduced if a base or an acid is reacted with the group. The salt thusobtained represents a pharmacologically acceptable salt.

Preferred examples of a pharmacologically acceptable “basic salt” of acompound include an alkali metal salt such as a sodium salt, a potassiumsalt and a lithium salt; an alkaline earth metal salt such as amagnesium salt and a calcium salt; an organic base salt such as aN-methyl morpholine salt, a triethylamine salt, a tributylamine salt, adiisopropylethylamine salt, a dicyclohexylamine salt, a N-methylpiperidine salt, a pyridine salt, a 4-pyrrolidinopyridine salt, and apicoline salt; and an amino acid salt such as a glycine salt, a lysinesalt, an arginine salt, an ornithine salt, glutamate, and aspartate.Preferably, an alkali metal salt is mentioned.

Preferred examples of a pharmacologically acceptable “acidic salt” of acompound include inorganic acid salts including a hydrohalic acid saltsuch as a hydrofluoride, a hydrochloride, a hydrobromide and ahydroiodide, a nitrate, a perchlorate, a sulfate and a phosphate;organic acid salts including a lower alkanesulfonate such as amethanesulfonate, a trifluoromethanesulfonate and an ethanesulfonate, anaryl sulfonate such as a benzenesulfonate and p-toluene sulfonate, anacetate, a malate, a fumarate, a succinate, a citrate, an ascorbate, atartrate, an oxalate and a maleate; and amino acid salts such as aglycine salt, a lysine salt, an arginine salt, an ornithine salt,glutamate and aspartate. Most preferably, a hydrohalic acid salt(particularly, hydrochloride) is mentioned.

The compound of the present invention or a pharmacologically acceptablesalt thereof sometimes absorbs water or adsorbs moisture or forms ahydrate when it is left alone in the air or by re-crystallization. Thesevarious hydrates, solvates and polymorphic compounds are also includedin the present invention.

The compound of the present invention, a pharmacologically acceptablesalt thereof or a solvate thereof may have various type of isomersincluding geometric isomers such as a cis isomer and a trans isomer,tautomers, and optical isomers such as d-form and l-form depending onthe types and combinations of substituents. However, unless otherwisespecified, all isomers, stereoisomers and a mixture of these isomers andstereoisomers in any mixing ratio are included in the compound of thepresent invention. A mixture of these isomers can be separated by aseparation means known in the art.

As the compound of the present invention, a labeled compound, morespecifically, a compound having 1 or 2 or more atoms substituted with anisotope (for example, 2H, 3H, 13C, 14C, 35S), is also included.

In the present invention, a so-called prodrug is also included. The termprodrug refers to a compound having a group that can be converted intoan amino group, a hydroxyl group or a carboxyl group by hydrolysis or inphysiological conditions. The groups involved in forming such prodrugsare described in Prog. Med., vol. 5, 2157-2161 pages, 1985. Morespecifically, the prodrug can be as mentioned below.

(1) When an amino group is present in the compound, a compound having anacylated, alkylated or phosphorylated amino group (for example, acompound having an eicosanoylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidyl methylated, pivaloyloxymethylated ortert-butylated amino group) or the like can be mentioned.

(2) When a hydroxyl group is present in the compound, a compound havingan acylated, alkylated, phosphorylated or borated hydroxyl group (forexample, a compound having an acetylated, palmitoylated, propanoylated,pivaloylated, succinylated, fumarylated, alanylated ordimethylaminomethylcarbonylated hydroxyl group) or the like can bementioned.

(3) When a carboxyl group is present in the compound, a compound havingan esterified or amidated carboxyl group (for example, a compound havingan ethyl-esterified, phenyl-esterified, carboxymethyl-esterified,dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified,ethoxycarbonyloxyethyl-esterified, amidated or methylamidated carboxylgroup) or the like can be mentioned.

Herein, unless otherwise stated, the value of the powder X-raydiffraction analysis is a value obtained using Cu-Kα rays. When X-raysother than Cu-Kα rays are used, 2θ(°) varies according to the equation2d sin θ=nλ, in which d is the distance between the two surfaces, n isan integer, and λ is the wavelength of the X-ray. However, these arejust representations of the crystal of the present invention by othersubstantially equivalent expression methods, and are included in thescope of the present invention, which can be easily understood by thoseskilled in the crystal art. In addition, the relative intensity of thepeaks indicated by these charts may vary depending on, for example, thedegree of crystallization or the method of preparation of the sample.2θ(°) does not substantially vary, but may vary within a range of error(generally, a range of ±0.2°) which is recognized by those skilled inthe crystal art. In the characteristic peak of powder X-ray diffractionrepresented by an angle 2θ, The term “about” indicates ±0.2°, and inanother embodiment, ±0.1°.

The value of the powder X-ray diffraction analysis should not beinterpreted strictly, since, due to the nature of the data, the crystallattice spacing and overall pattern are important for determining theidentity of the crystal, and the relative intensity can vary somewhatdepending on the direction of crystal growth, grain size, andmeasurement conditions.

(Production Method)

Now, the production method will be described. However, the presentinvention is not limited by the methods described below.

When the structure represented by J in the compound of the generalformula (1) is the following 1,2,3-triazole:

the compound (A-V) of the present invention can be produced, forexample, using the following Method A.

[Method A]

Method A is a method of producing the compound (A-V) of the presentinvention

wherein the symbols used in the formula are as defined above. P^(n)represents an amino group-protecting group.

(Step A1) Step of Deprotecting Amino Group

This is a step of obtaining a compound (A-II) by deprotecting the aminogroup-protecting group from a compound (A-I). For example, when theprotecting group is a tert-butoxycarbonyl group, the compound (A-II) canbe obtained by dissolving the compound (A-I) in a solvent and adding anacid. The reaction temperature is usually about −20 to 100° C. and thereaction time is usually about 1 to 24 hours.

Examples of the acid used include trifluoroacetic acid and hydrochloricacid.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include dichloromethane,chloroform, methanol, ethyl acetate, and 1,4-dioxane, and a mixture ofthese.

(Step A2) Step of Converting Amino Group into Azide Group

This is a step of converting the amino group of the compound (A-II) intoan azide group. A compound (A-III) can be obtained by dissolving thecompound (A-II) in a solvent and reacting with tert-butyl nitrate todiazotize, and then converting it into an azide group by addition oftrimethylsilylazide and trifluoroacetic acid.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include water, acetonitrile,dichloromethane, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, aceticacid, and hydrochloric acid, and a mixture of these. The reactiontemperature is usually about 0 to 60° C. and the reaction time isusually about 0.5 to 24 hours.

This step can also be performed, for example, by stirring2-azido-1,3-dimethylimidazolinium hexafluorophosphate and triethylaminein a dichloromethane solvent at about 0 to 60° C. for about 0.5 to 24hours.

(Step A3) Step of Forming Triazole Ring

This is a step of producing the compound (A-V) by reacting the compound(A-III) with a corresponding alkyne (A-IV). The compound (A-V) can beobtained by dissolving the corresponding alkyne (A-IV) and the compound(A-III) in a solvent, and adding diisopropylethylamine and copper iodideat 0° C. to room temperature. The reaction temperature is usually aboutroom temperature to 80° C. and the reaction time is usually about 1 to24 hours.

Examples of the base used include tertiary amines such asdiisopropylethylamine and triethylamine.

Examples of the metal catalyst used include copper iodide and coppersulfate.

Examples of the ligand used includetris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine andtris(benzimidazole)amine.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include water, methanol,ethanol, tert-butyl alcohol, tetrahydrofuran, 1,4-dioxane, acetonitrile,ethyl acetate, acetone, dichloromethane, N,N-dimethylformamide, toluene,and a mixture of these.

When the structure represented by G in the compound of general formula(1) of the present invention is the following 1,2,4-triazole:

wherein the symbol used in the formula is the same as defined above,

a compound equivalent to the compound (A-I) that is used in Method A canbe produced, for example, using the following Method B.

[Method B]

Method B is a method of producing a compound (B-III) (equivalent to thecompound (A-I) that is used in Method A).

wherein the symbols used in the formula are the same as defined above.P^(n) represents an amino group-protecting group.

(Step B1) Step of Forming Triazole Ring

This is a step of producing the compound (B-III) by reacting a compound(B-I) with an alkylating agent such as methyl iodide to convert it intothe corresponding thioimidate, and reacting the thioimidate with acompound (B-II).

The solvent used in the reaction of the compound (B-I) and methyl iodideis not particularly limited as long as it does not inhibit the reaction,and examples thereof include tetrahydrofuran and 1,4-dioxane. Thereaction temperature is usually about room temperature to 80° C. and thereaction time is usually about 1 to 24 hours.

Furthermore, the solvent used in the reaction of the thioimidate and thecompound (B-II) is not particularly limited as long as it does notinhibit the reaction, and examples thereof include tetrahydrofuran and1,4-dioxane. The reaction temperature is usually about room temperatureto 120° C. and the reaction time is usually about 1 to 24 hours.

[Method C]

Method C is a method of producing a compound (C-III) (equivalent to thecompound (B-I) that is used in Method B).

wherein the symbols used in the formula are the same as defined above.

(Step C1) Step of Forming Amide by Condensation

This is a step of (i) producing a compound (C-II) by activating acarboxylic acid (C-I), which is commercially available or can besynthesized by a known method, as an acid chloride, and reacting theacid chloride with the corresponding amine, or (ii) producing a compound(C-II) by reacting the carboxylic acid (C-I) with the correspondingamine in the presence of a condensing agent.

In the case of (i), the compound (C-II) can be obtained, for example, byadding oxalyl chloride and a small amount of dimethylformamide to asolution of the carboxylic acid (C-I) in dichloromethane at 0° C. toroom temperature, allowing to stand still for a while, and then addingthe corresponding amine and a base such as pyridine at 0° C. to roomtemperature. The reaction temperature is usually about room temperatureto 80° C. and the reaction time is usually about 1 to 24 hours.

In the case of (ii), the compound (C-II) can be obtained, for example,by adding a base and a condensing agent to a solution of the carboxylicacid (C-I) and a corresponding amine in dimethylformamide ordichloromethane. The reaction temperature is usually about roomtemperature to 80° C. and the reaction time is usually about 1 to 24hours.

Examples of the base used include tertiary amines such asdiisopropylethylamine.

Examples of the condensing agent used include4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(DMT-MM), N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uroniumhexafluorophosphate (HBTU), hexafluorophosphateO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium (HATU), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI).

(Step C2) Step of Thiocarbonylation

This is a step of obtaining a compound (C-III) by reacting the compound(C-II) with a sulfurizing agent such as Lawesson's reagent in a solvent.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include tetrahydrofuran,1,4-dioxane, and a mixture of these. The reaction temperature is usuallyabout 0 to 100° C. and the reaction time is usually about 0.5 to 24hours.

[Method D]

Method D is a method of producing a compound (D-II) (equivalent to thecompound (B-II) that is used in Method B).

wherein the symbols used in the formula are the same as defined above.P^(c) represents a carboxyl group-protecting group.

(Step D1) Step of Forming Hydrazide

This is a step of producing the compound (D-II) by heating a compound(D-I) that is commercially available or can be synthesized by a knownmethod, with hydrazine in a solvent.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include methanol, ethanol,water, and a mixture of these. The reaction temperature is usually aboutroom temperature to 100° C. and the reaction time is usually about 0.5to 24 hours.

[Method E]

Method E is a method of producing a compound (E-X) (equivalent to thecompound (A-V) in Method A) of the present invention. In this method,for convenience, the case where the structure represented by G in thecompound of the general formula (1) of the present invention is1,2,4-triazole is described as an example. However, even when thestructure represented by G is another 5-membered aromatic heterocycliccompound, the target compound can be produced in the same manner by amethod usually used in this field.

wherein the symbols used in the formula are the same as defined above.P^(c) represents a carboxyl group-protecting group or a hydroxylgroup-protecting group. P^(n) represents an amino group-protectinggroup.

(Step E1) Step of Forming Hydrazide

This is a step of producing a compound (E-II) from a compound (E-I) thatis commercially available or can be synthesized by a known method, underthe same conditions as in Step D1 of Method D.

(Step E2) Step of Forming Triazole Ring

This is a step of producing a compound (E-IV) from the compound (E-II)and a compound (E-III) (equivalent to (C-III) in Method C) under thesame conditions as in Step B1 of Method B.

(Step E3) Step of Deprotecting Amino Group-Protecting Group

This is a step of obtaining a compound (E-V) by deprotecting the aminogroup-protecting group from the compound (E-IV) under the sameconditions as in Step A1 of Method A.

(Step E4) Step of Converting Amino Group into Azide Group

This is a step of obtaining a compound (E-VI) from the compound (E-V) byconverting an amino group into an azide group under the same conditionsas in Step A2 of Method A.

(Step E5) Step of Forming Triazole Ring

This is a step of producing a compound (E-VIII) from the compound (E-VI)by reacting the compound (E-VI) with a corresponding alkyne (E-VII)under the same conditions as in Step A3 of Method A.

(Step E6) This is a step of obtaining a compound (E-IX) by deprotectingthe hydroxyl group-protecting group from the compound (E-VIII). Forexample, when the protecting group is a tert-butyldiphenylsilyl group,the compound (E-IX) can be obtained by dissolving the compound (E-VIII)in a solvent and adding tetra-n-butylammonium fluoride. The reactiontemperature is usually about 0 to 80° C. and the reaction time isusually about 0.5 to 24 hours.

Examples of the reagent used include hydrochloric acid, sulfuric acid,hydrofluoric acid, p-toluenesulfonic acid (PPTS), acetic acid,trifluoroacetic acid, tetra-n-butylammonium fluoride, potassiumfluoride, cerium fluoride, hydrogen fluoride, and hydrogenfluoride-pyridine.

The solvents are not particularly limited as long as they do not inhibitthe reaction, and examples thereof include methanol, ethanol, diethylether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile,water, and a mixture of these.

(Step E7) Step of Etherification by Mitsunobu Reaction

This is a step of obtaining a compound (E-X) from the compound (E-IX) byuse of the corresponding alcohol in the presence ofcyanomethyltributylphosphorane.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include tetrahydrofuran,1,4-dioxane, toluene and a mixture of these. The reaction temperature isusually about 0 to 120° C. and the reaction time is usually about 0.5 to24 hours.

Furthermore, in this step, the compound (E-X) can be obtained from thecompound (E-IX) by use of a corresponding alcohol in the presence ofphosphine and azodicarboxylate or diazodicarboxamide. The reactiontemperature is usually about 0 to 100° C. and the reaction time isusually about 0.5 to 24 hours.

[Method F]

Method F is a method of producing the compound (F-VI) of the presentinvention

wherein the symbols used in the formula are the same as defined above. Lrepresents a leaving group. W represents, each independently, —CH₂—,—O—, or —NMe—.

(Step F1) Step of Alkylation

This is a step of producing a compound (F-II) from a compound (F-I) thatis commercially available or can be synthesized by a known method, usingthe corresponding alkyl halide in a solvent in the presence of anorganolithium reagent.

Examples of the organolithium reagent include n-butyllithium, lithiumdiisopropylamide, lithium hexamethyldisilazide, and lithium2,2,6,6-tetramethylpiperidine.

The solvents are not particularly limited as long as they do not inhibitthe reaction, and examples thereof include diethyl ether,tetrahydrofuran, toluene, n-hexane, and a mixture of these.

The reaction temperature is usually about −78 to 100° C., and thereaction time is usually about 1 to 48 hours.

(Step F2) Step of Deprotecting Amino Group-Protecting Group

This is a step of obtaining a compound (F-III) by deprotecting the aminogroup-protecting group from the compound (F-II). When the protectinggroup is a p-methoxybenzyl group, the compound (F-III) can be obtainedby dissolving the compound (F-II) in an acid and heating.

Examples of the acid used include trifluoroacetic acid and hydrochloricacid.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include dichloromethane,chloroform, methanol, ethyl acetate, 1,4-dioxane and a mixture of these.The reaction temperature is usually about 100 to 150° C. and thereaction time is usually about 1 to 48 hours.

(Step F3) Step of Thiocarbonylation

This is a step of obtaining a compound (F-IV) by reacting the compound(F-III) with a sulfurizing agent such as Lawesson's reagent in a solventunder the same conditions as in Step C2 of Method C.

(Step F4) Step of Forming Triazole Ring

This is a step of producing the compound (F-VI) by reacting the compound(F-IV) with an alkylating agent such as methyl iodide to convert it intothe corresponding thioimidate, and reacting the thioimidate with acorresponding compound (F-V) under the same conditions as in Step B1 ofMethod B.

[Method G]

Method G is a method of producing the compound (G-V) of the presentinvention.

wherein the symbols used in the formula are the same as defined above. Wrepresents, each independently, —CH₂—, —O—, or —NMe—.

(Step G1) Step of Etherification by Mitsunobu Reaction

This is a step of producing a compound (G-II) from a compound (G-I) thatis commercially available or can be synthesized by a known method, underthe same conditions as in Step E7 of Method E.

(Step G2) Step of Thiocarbonylation

This is a step of obtaining a compound (G-III) by reacting the compound(G-II) with a sulfurizing agent such as Lawesson's reagent in a solventunder the same conditions as in Step C2 of Method C.

(Step G3) Step of Forming Triazole Ring

This is a step of producing the compound (G-V) by reacting the compound(G-III) with an alkylating agent such as methyl iodide to convert itinto the corresponding thioimidate, and reacting the thioimidate with acompound (G-IV) under the same conditions as in Step B1 of Method B.

When the structure represented by J in the compound of the presentinvention is the following 1,2,3-triazole:

the compound (F-V) that is used in Method F or the compound (G-IV) thatis used in Method G can be produced, for example, using the followingMethod H.

[Method H]

Method H is a method of producing a compound (H-V) (equivalent to thecompound (F-V) that is used in Method F or the compound (G-IV) that isused in Method G).

wherein the symbols used in the formula are as defined above. P^(c)represents a carboxyl group-protecting group or a hydroxylgroup-protecting group.

(Step H1) Step of Converting Amino Group into Azide Group

This is a step of obtaining a compound (H-II) from a compound (H-I) thatis commercially available or can be synthesized by a known method, byconverting an amino group into an azide group under the same conditionsas in Step A2 of Method A.

(Step H2) Step of Forming Triazole Ring

This is a step of producing a compound (H-IV) from the compound (H-II)by reacting the compound (H-II) with a corresponding alkyne (H-III)under the same conditions as in Step A3 of Method A.

(Step H3) Step of Forming Hydrazide

This is a step of producing a compound (H-V) from a compound (H-IV)under the same conditions as in Step D1 of Method D.

When the structure represented by J in the compound of the presentinvention is the following pyrazole:

the compound (I-VI) of the present invention can be produced, forexample, using the following Method I.

[Method I]

Method I is a method of producing the compound (I-VI) of the presentinvention. In this method, for convenience, the case where the structurerepresented by G in the compound of the general formula (1) of thepresent invention is 1,2,4-triazole is described as an example. However,even when the structure represented by G is another 5-membered aromaticheterocyclic compound, the target compound can be produced in the samemanner by a method usually used in this field.

wherein the symbols used in the formula are the same as defined above. Lrepresents a leaving group. B^(h) represents boronic acid or boronicacid pinacol ester.

(Step I1) Step of Thiocarbonylation

This is a step of obtaining a compound (I-II) by reacting a compound(I-I) that is commercially available or can be synthesized by a knownmethod, with a sulfurizing agent such as Lawesson's reagent in a solventunder the same conditions as in Step C2 of Method C.

(Step I2) Step of Forming Triazole Ring

This is a step of producing a compound (I-IV) by reacting the compound(I-II) with an alkylating agent such as methyl iodide to convert it intothe corresponding thioimidate, and reacting the thioimidate with acompound (I-III) (equivalent to the compound (D-II) produced in MethodD) under the same conditions as in Step B1 of Method B.

(Step I3) Step of Coupling Reaction Using Transition Metal Catalyst

This is a step of obtaining a compound (I-V) by reacting the compound(I-IV) with the corresponding pyrazole using a transition metal as acatalyst in the presence of a base.

Examples of the transition metal catalyst used include copper iodide,copper chloride, and copper acetate.

Examples of the base include triethylamine, diisopropylethylamine,1,8-diazabicyclo[5.4.0]-7-undecene (DBU),1,5-diazabicyclo[4.3.0]-5-nonene (DBN), potassium hydrogen carbonate,sodium hydrogen carbonate, potassium carbonate, sodium carbonate, cesiumcarbonate, potassium hydroxide, sodium hydroxide, potassium phosphateand sodium phosphate.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include methanol, ethanol,tetrahydrofuran, 1,4-dioxane, water, N,N-dimethylformamide,dimethylsulfoxide, toluene and a mixture of these. The reactiontemperature is usually about 60 to 200° C. and the reaction time isusually about 0.5 to 24 hours.

(Step I4) Step of Coupling Reaction Using Transition Metal Catalyst

This is a step of obtaining the compound (I-VI) from the compound (I-V)by use of a palladium catalyst and a corresponding boronic acid orboronic acid pinacol ester in the presence of a base.

Examples of the palladium catalyst used include tetrakis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium,tris(dibenzylideneacetone)dipalladium, palladium acetate, acetylacetonepalladium and bis(triphenylphosphine)palladium dichloride.

Examples of the base used include triethylamine, diisopropylethylamine,1,8-diazabicyclo[5.4.0]-7-undecene (DBU),1,5-diazabicyclo[4.3.0]-5-nonene (DBN), potassium hydrogen carbonate,sodium hydrogen carbonate, potassium carbonate, sodium carbonate,potassium hydroxide, sodium hydroxide, potassium phosphate and sodiumphosphate.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include methanol, ethanol,tetrahydrofuran, 1,4-dioxane, water, N,N-dimethylformamide,dimethylsulfoxide, toluene and a mixture of these. The reactiontemperature is usually about 60 to 120° C. and the reaction time isusually about 0.5 to 24 hours.

[Method J]

Method J is a method of producing a compound (J-V) (equivalent to thecompound (I-V) that is used in Method I).

wherein the symbols used in the formula are the same as defined above.P^(c) represents a carboxyl group-protecting group. L represents aleaving group.

(Step J1) Step of Introducing Pyrazole Ring by Substitution Reaction

This is a step of obtaining a compound (J-II) by reacting a compound(J-I) that is commercially available or can be synthesized by a knownmethod, with the corresponding pyrazole in the presence of a base.

Examples of the base include triethylamine, diisopropylethylamine,1,8-diazabicyclo[5.4.0]-7-undecene (DBU),1,5-diazabicyclo[4.3.0]-5-nonene (DBN), potassium hydrogen carbonate,sodium hydrogen carbonate, potassium carbonate, sodium carbonate, cesiumcarbonate, potassium hydroxide, sodium hydroxide, potassium phosphateand sodium phosphate.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include methanol, ethanol,tetrahydrofuran, 1,4-dioxane, water, N,N-dimethylformamide,dimethylsulfoxide, toluene, and a mixture of these. The reactiontemperature is usually about 60 to 100° C. and the reaction time isusually about 1 to 24 hours.

(Step J2) Step of Forming Hydrazide

This is a step of producing a compound (J-III) from the compound (J-II)under the same conditions as in Step D1 of Method D.

(Step J3) Step of Forming Triazole Ring

This is a step of producing a compound (J-V) by reacting a compound(J-IV) with an alkylating agent such as methyl iodide to convert it intothe corresponding thioimidate, and reacting the thioimidate with thecompound (J-III) under the same conditions as in Step B1 of Method B.

[Method K]

Method K is a method of producing a compound (K-II) (equivalent to thecompound (J-IV) that is used in Method J).

wherein the symbols used in the formula are the same as defined above.

(Step K1) Step of Thiocarbonylation

This is a step of obtaining a compound (K-II) by reacting a compound(K-I) that is commercially available or can be synthesized by a knownmethod, with a sulfurizing agent such as Lawesson's reagent in a solventunder the same conditions as in Step C2 of Method C.

When the structure represented by J in the compound of the presentinvention is the following imidazole:

the compound (L-V) of the present invention can be produced, forexample, using the following Method L.

[Method L]

Method L is a method of producing the compound (L-V) of the presentinvention. In this method, for convenience, the case where the structurerepresented by G in the compound of the general formula (1) of thepresent invention is 1,2,4-triazole is described as an example. However,even when the structure represented by G is another 5-membered aromaticheterocyclic compound, the target compound can be produced in the samemanner by a method usually used in this field.

wherein the symbols used in the formula are as defined above. P^(n)represents an amino group-protecting group. L represents a leavinggroup. B^(h) represents boronic acid or boronic acid pinacol ester.

(Step L1) Step of Coupling Reaction Using Transition Metal Catalyst

This is a step of obtaining a compound (L-II) from a compound (L-1) thatis commercially available or can be synthesized by a known method, byuse of a palladium catalyst and a corresponding boronic acid or boronicacid pinacol ester in the presence of a base under the same conditionsas in Step 14 of Method I.

(Step L2) Step of Deprotecting Amino Group-Protecting Group

This is a step of obtaining a compound (L-III) by deprotecting the aminogroup-protecting group from the compound (L-II). When the protectinggroup is a dimethylaminosulfonyl group, the compound (L-III) can beobtained by adding an acid to the compound (L-II).

Examples of the acid used include concentrated hydrochloric acid.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include dichloromethane,chloroform, methanol, ethyl acetate, 1,4-dioxane and a mixture of these.The reaction temperature is usually about 0 to 100° C. and the reactiontime is usually about 15 minutes to 12 hours.

(Step L3) Step of Coupling Reaction Using Transition Metal Catalyst

This is a step of obtaining the compound (L-V) by reacting the compound(L-III) with a compound (L-IV) (equivalent to the compound (I-IV) thatis produced in Method I) using a transition metal such as copper as acatalyst in the presence of a base under the same conditions as in StepI3 of Method I.

When the structure represented by J in the compound of the presentinvention is the following 1,2,3-triazole:

the compound (M-X) of the present invention can be produced, forexample, using the following Method M.

[Method M]

Method M is a method of producing the compound (M-X) of the presentinvention. In this method, for convenience, the case where the structurerepresented by G in the compound of the general formula (1) of thepresent invention is 1,2,4-triazole is described as an example. However,even when the structure represented by G is another 5-membered aromaticheterocyclic compound, the target compound can be produced in the samemanner by a method usually used in this field.

wherein the symbols used in the formula are as defined above. P^(c)represents a carboxyl group-protecting group.

(Step M1) Step of Forming Amide by Condensation

This is a step of producing a compound (M-II) from a compound (M-I) thatis commercially available or can be synthesized by a known method, andthe corresponding amine under the same conditions as in Step C1 ofMethod C.

(Step M2) Step of Thiocarbonylation

This is a step of obtaining a compound (M-III) by reacting the compound(M-II) with a sulfurizing agent such as Lawesson's reagent in a solventunder the same conditions as in Step C2 of Method C.

(Step M3) Step of Forming Triazole Ring

This is a step of producing a compound (M-V) by reacting a compound(M-III) with an alkylating agent such as methyl iodide to convert itinto a corresponding thioimidate, and reacting the thioimidate with acompound (M-IV) (equivalent to the compound (D-II) that is used inMethod D) under the same conditions as in Step B1 of Method B.

(Step M4) Step of Reducing Ester to Form Alcohol

This is a step of producing a compound (M-VI) by reacting the compound(M-V) with a reducing agent in a solvent.

Examples of the reducing agent used include lithium aluminium hydride(LAH) and diisobutylaluminium hydride (DIBAL).

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include toluene, diethylether, and tetrahydrofuran, and a mixture of these. The reactiontemperature is usually about −78 to 100° C. and the reaction time isusually about 0.5 to 24 hours.

(Step M5) Step of Oxidizing Alcohol to Form Aldehyde

This is a step of producing a compound (M-VII) by reacting the compound(M-VI) with an oxidizing agent in a solvent.

Examples of the oxidizing agent used include manganese dioxide,potassium permanganate, pyridinium chlorochromate (PCC), pyridiniumdichromate (PDC), a Dess-Martin reagent,2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO),2-azaadamantane-N-oxyl (AZADO), and tetrapropylammonium perruthenate(TPAP).

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include dichloromethane,toluene, diethyl ether, tetrahydrofuran, acetonitrile, acetone,N,N-dimethylformamide, and dimethyl sulfoxide, and a mixture of these.The reaction temperature is usually about −20 to 100° C. and thereaction time is usually about 0.5 to 24 hours.

(Step M6) Step of Increasing Carbon in Aldehyde to Form Alkyne

This is a step of producing a compound (M-VIII) by reacting the compound(M-VII) with an α-diazophosphonate compound in the presence of a base.

Examples of the α-diazophosphonate compound includedimethyl(1-diazo-2-oxopropyl)phosphonate (Ohira-Bestmann reagent).

Examples of the base used include potassium hydrogen carbonate, sodiumhydrogen carbonate, potassium carbonate, and sodium carbonate.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include methanol, ethanol,diethyl ether, tetrahydrofuran, and acetonitrile, and a mixture ofthese. The reaction temperature is usually about −20 to 100° C. and thereaction time is usually about 0.5 to 24 hours.

(Step M7) Step of Forming Triazole Ring

This is a step of producing the compound (M-X) by reacting a compound(M-VIII) with the corresponding azide (M-IX) under the same conditionsas in Step A3 of Method A.

[Method N]

Method N is a method of producing a compound (N-VIII) (equivalent to thecompound (M-VIII) that is used in Method M).

wherein the symbols used in the formula are the same as defined above.P^(c) represents a carboxyl group-protecting group or a hydroxylgroup-protecting group.

(Step N1) Step of Forming Triazole Ring

This is a step of producing a compound (N-III) by reacting a compound(N-I) (equivalent to the compound (M-III) that is used in Method M) withan alkylating agent such as methyl iodide to convert it into thecorresponding thioimidate, and reacting the thioimidate with a compound(N-II) (equivalent to the compound (E-II) that is used in Method E)under the same conditions as in Step B1 of Method B.

(Step N2) Step of reducing ester to form alcohol

This is a step of producing a compound (N-IV) by reacting the compound(N-III) with a reducing agent in a solvent under the same conditions asin Step M4 of Method M.

(Step N3) Step of Oxidizing Alcohol to Form Aldehyde

This is a step of producing a compound (N-V) by reacting the compound(N-IV) with an oxidizing agent in a solvent under the same conditions asin Step M5 of Method M.

(Step N4) Step of Increasing Carbon in Aldehyde to Form Alkyne

This is a step of producing a compound (N-VI) by reacting the compound(N-V) with an α-diazophosphonate compound in the presence of a baseunder the same conditions as in Step M6 of Method M.

(Step N5) This is a step of obtaining a compound (N-VII) by deprotectingthe hydroxyl group of the compound (N-VI) under the same conditions asin Step E6 of Method E.

(Step N6) Step of Etherification by Mitsunobu Reaction

This is a step of obtaining a compound (N-VIII) by reacting the compound(N-VII) with the corresponding alcohol in the presence of cyanomethylenetributylphosphorane under the same conditions as in Step E7 of Method E.

When the structure represented by J in the compound of the presentinvention is the following pyrazole:

the compound (O-VIII) of the present invention can be produced, forexample, using the following Method O.

[Method O]

Method O is a method of producing the compound (O-VIII) of the presentinvention. In this method, for convenience, the case where the structurerepresented by G in the compound of the general formula (1) of thepresent invention is 1,2,4-triazole is described as an example. However,even when the structure represented by G is another 5-membered aromaticheterocyclic compound, the target compound can be produced in the samemanner by a method usually used in this field.

wherein the symbols used in the formula are as defined above. P^(c)represents a carboxyl group-protecting group or a hydroxylgroup-protecting group. P^(n) represents an amino group-protectinggroup. L represents a leaving group. B^(h) represents boronic acid orboronic acid pinacol ester.

(Step O1) Step of Coupling Reaction Using Transition Metal Catalyst

This is a step of obtaining a compound (O-III) from a compound (O-I)that is commercially available or can be synthesized by a known method,by use of a palladium catalyst and the compound (O-II) having thecorresponding boronic acid or boronic acid pinacol ester in the presenceof a base under the same conditions as in Step I4 of Method I.

(Step O2) Step of Forming Hydrazide

This is a step of producing a compound (O-IV) from a compound (O-III)under the same conditions as in Step D1 of Method D.

(Step O3) Step of Forming Triazole Ring

This is a step of producing a compound (O-VI) by reacting a compound(O-V) (equivalent to the compound (K-II) that is used in Method K) withan alkylating agent such as methyl iodide to convert it into thecorresponding thioimidate, and reacting the thioimidate with thecompound (O-IV) under the same conditions as in Step B1 of Method B.

(Step O4) Step of Deprotecting Amino Group-Protecting Group

This is a step of obtaining a compound (O-VII) by deprotecting an aminogroup-protecting group from the compound (O-VI). When the protectinggroup is a tetrahydropyranyl group, the compound (O-VII) can be obtainedby dissolving the compound (O-VI) in a solvent and adding an acid.

Examples of the acid include hydrochloric acid, sulfuric acid, aceticacid, p-toluenesulfonic acid and pyridinium p-toluenesulfonate.

Examples of the solvent include methanol, ethanol, tetrahydrofuran,1,4-dioxane, ethyl acetate, water, and a mixture of these. The reactiontemperature is usually about 0 to 80° C. and the reaction time isusually about 0.5 to 24 hours.

(Step O5) Step of Introducing Substituent by Substitution Reaction

This is a step of obtaining the compound (O-VIII) by reacting thecompound (O-VII) with a compound having the corresponding leaving groupin the presence of a base under the same conditions as in Step J1 ofMethod J.

[Method P]

Method P is a method of producing a compound (P-VII) (equivalent to thecompound (O-VIII) in Method O) of the present invention. In this method,for convenience, the case where the structure represented by G in thecompound of the general formula (1) of the present invention is1,2,4-triazole is described as an example. However, even when thestructure represented by G is another 5-membered aromatic heterocycliccompound, the target compound can be produced in the same manner by amethod usually used in this field.

wherein the symbols used in the formula are the same as defined above.P-II represents a mixture of E and Z isomers.

(Step P1) Step of Increasing Carbon in Aldehyde to Form Enol Ether

This is a step of producing a compound (P-II) by reacting a compound(P-I) (equivalent to the compound (M-VII) that is used in Method M) witha phosphonate compound (such as (methoxymethyl)triphenylphosphoniumchloride) in the presence of a base.

Examples of the base used include sodium methylate, potassiumtert-butoxide, sodium hydride, potassium hydride, sodiumbistrimethylsilylamide, and lithium bistrimethylsilylamide.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include diethyl ether,tetrahydrofuran, toluene, hexane, N,N-dimethylformamide, dimethylsulfoxide, acetic acid, and a mixture of these. The reaction temperatureis usually about 0 to 80° C. and the reaction time is usually about 5minutes to 24 hours.

(Step P2) Step of Hydrolyzing Enol Ether to Form Aldehyde

This is a step of producing a compound (P-III) by hydrolyzing a compound(P-II) with an acid in a solvent.

Examples of the acid used include hydrochloric acid, sulfuric acid,phosphoric acid, nitric acid, perchloric acid, p-toluenesulfonic acid(PPTS), methanesulfonic acid, acetic acid, and formic acid.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include water, acetone,methyl ethyl ketone, diethyl ether, tetrahydrofuran, 1,4-dioxane,N,N-dimethylformamide, dimethyl sulfoxide, toluene, dichloromethane, anda mixture of these. The reaction temperature is usually about 0 to 100°C. and the reaction time is usually about 5 minutes to 24 hours.

(Step P3) Step of Forming Exomethylene Aldehyde

This is a step of producing a compound (P-IV) by reacting a compound(P-III) with a corresponding aldehyde (for example, formaldehyde) in thepresence of a catalyst.

Examples of the catalyst used include L-proline, dimethylamine,diethylamine, diethanolamine, morpholine, piperidine, pyrrolidine,pyrazole, and indole.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include water, ethanol,isopropyl alcohol, tetrahydrofuran, N,N-dimethylformamide, toluene,dichloromethane, acetic acid, and a mixture of these. The reactiontemperature is usually about 0 to 100° C. and the reaction time isusually about 5 minutes to 72 hours.

(Step P4) Step of Oxidizing Exomethylene to Form Epoxide

This is a step of producing a compound (P-V) by reacting a compound(P-IV) with an oxidizing agent in a solvent.

Examples of the oxidizing agent used include peracetic acid,trifluoroperacetic acid, metachloroperacetic acid, hydrogen peroxide,benzoyl peroxide, tert-butyl hydroperoxide, tert-amyl hydroperoxide, andoxone.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include dichloromethane,chloroform, diethyl ether, toluene, xylene, acetone, acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, acetic acid and a mixture ofthese. The reaction temperature is usually about −78 to 100° C. and thereaction time is usually about 5 minutes to 48 hours.

(Step P5) Step of Forming Pyrazole Ring

This is a step of producing a compound (P-VII) by reacting a compound(P-V) with a corresponding hydrazine (P-VI) or a salt adduct thereof ina solvent.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include water, methanol,ethanol, isopropyl alcohol, tetrahydrofuran, N,N-dimethylformamide,toluene, dichloromethane, and a mixture of these. The reactiontemperature is usually about 0 to 100° C. and the reaction time isusually about 0.5 to 72 hours.

[Method Q]

Method Q is a method of producing the compound (Q-IX) (equivalent to thecompound (O-VIII) that is used in Method O) of the present invention. Inthis method, for convenience, the case where the structure representedby G in the compound of the general formula (1) of the present inventionis 1,2,4-triazole is described as an example. However, even when thestructure represented by G is another 5-membered aromatic heterocycliccompound, the target compound can be produced in the same manner by amethod usually used in this field.

wherein the symbols used in the formula are as defined above. P^(c)represents a hydroxyl group-protecting group. Q-II represents a mixtureof E and Z isomers.

(Step Q1) Step of Increasing Carbon in Aldehyde to Form Enol Ether

This is a step of producing a compound (Q-II) by reacting a compound(Q-I) (equivalent to the compound (N-V) that is used in Method N) with aphosphonate compound (for example, (methoxymethyl)triphenylphosphoniumchloride) in the presence of a base under the same conditions as in StepP1 of Method P.

(Step Q2) Step of Hydrolyzing Enol Ether to Form Aldehyde

This is a step of producing a compound (Q-III) by hydrolyzing thecompound (Q-II) with an acid in a solvent under the same conditions asin Step P2 of Method P.

(Step Q3) Step of Forming Exomethylene Aldehyde

This is a step of producing a compound (Q-IV) by reacting the compound(Q-III) with a corresponding aldehyde (for example, formaldehyde) in thepresence of a catalyst under the same conditions as in Step P3 of MethodP.

(Step Q4) Step of Oxidizing Exomethylene to Form Epoxide

This is a step of producing a compound (Q-V) by reacting the compound(Q-IV) with an oxidizing agent in a solvent under the same conditions asin Step P4 of Method P.

(Step Q5) Step of Forming Pyrazole Ring

This is a step of producing a compound (Q-VII) by reacting the compound(Q-V) with the corresponding hydrazine (Q-VI) in a solvent under thesame conditions as in Step P5 of Method P.

(Step Q6) This is a step of obtaining a compound (Q-VIII) bydeprotecting the hydroxyl group of the compound (Q-VII) under the sameconditions as Step E6 of Method E.

(Step Q7) Step of Etherification by Mitsunobu Reaction

This is a step of obtaining the compound (Q-IX) by reacting the compound(Q-VIII) with the corresponding alcohol in the presence ofcyanomethylene tributylphosphorane under the same conditions as in StepE7 of Method E.

[Method R]

Method R is a method of producing a compound (R-V) (equivalent to thecompound (P-VI) in Method P and the compound (Q-VI) in Method Q).

wherein the symbols used in the formula are as defined above. P^(n)represents an amino group-protecting group.

(Step R1) Step of Forming N-Protected Hydrazine by Reductive Amination

This is a step of producing a compound (R-IV) by reacting a compound(R-I) that is commercially available or can be synthesized by a knownmethod, with N-protected hydrazine (for example, benzyl carbazate ortert-butyl carbazate) and a reducing agent in a solvent.

Examples of the reducing agent to be used include sodiumtriacetoxyborohydride, sodium cyanoborohydride, sodium borohydride,lithium borohydride, pyridine borane, and 2-picolineborane.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include methanol, ethanol,isopropyl alcohol, tetrahydrofuran, acetonitrile, dichloromethane,chloroform, 1,2-dichloroethane, N,N-dimethylformamide, water, aceticacid, and a mixture of these. The reaction temperature is usually about−20 to 100° C. and the reaction time is usually about 5 minutes to 72hours.

In this step, the reaction may be promoted by adding an acid to thereaction system.

(Step R2) Step of Forming N-Protected Hydrazine Using OxaziridineReagent

This is a step of producing a compound (R-IV) by reacting a compound(R-II) that is commercially available or can be synthesized by a knownmethod, with an oxaziridine that is commercially available or can besynthesized by a known method, in a solvent.

Examples of the base used include triethylamine, diisopropylethylamine,1,8-diazabicyclo[5.4.0]-7-undecene (DBU), and1,5-diazabicyclo[4.3.0]-5-nonene (DBN).

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include tetrahydrofuran,1,4-dioxane, dichloromethane, N,N-dimethylacetamide, and a mixture ofthese. The reaction temperature is usually about −78 to 100° C. and thereaction time is usually about 0.5 to 24 hours.

(Step R3) Step of Deprotecting Amino Group-Protecting Group

This is a step of obtaining a compound (R-V) by deprotecting an aminogroup-protecting group from the compound (R-IV).

(i) For example, when the protecting group is a tert-butoxycarbonyl(Boc) group, the compound (R-V) can be obtained by dissolving thecompound (R-IV) in a solvent and adding an acid. The reactiontemperature is usually about −20 to 100° C. and the reaction time isusually about 1 to 24 hours.

Examples of the acid used include trifluoroacetic acid and hydrochloricacid.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include dichloromethane,chloroform, methanol, ethyl acetate, and 1,4-dioxane, and a mixture ofthese.

(ii) The compound (R-V) can be obtained, for example, when theprotecting group is a benzyloxycarbonyl (Cbz) group, by dissolving thecompound (R-IV) in a solvent in the presence of a metal catalyst such as10% palladium carbon.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include tetrahydrofuran,1,4-dioxane, methanol, ethanol, acetic acid, and a mixture of these. Thereaction temperature is usually about room temperature to 60° C. and thereaction time is usually about 0.5 to 24 hours.

In this step, the reaction may be promoted by adding an acid to thereaction system.

[Method S]

Method S is a method of producing the compound (S-III) (equivalent tothe compound (O-VIII) that is used in Method O) of the presentinvention. In this method, for convenience, the case where the structurerepresented by G in the compound of the general formula (1) of thepresent invention is 1,2,4-triazole is described as an example. However,even when the structure represented by G is another 5-membered aromaticheterocyclic compound, the target compound can be produced in the samemanner by a method usually used in this field.

wherein the symbols used in the formula are the same as defined above. Lrepresents a leaving group.

(Step S1) Step of Converting Hydroxyl Group into Leaving Group

This is a step of producing a compound (S-II) by reacting a compound(S-I) (equivalent to the compound (Q-VIII) that is used in Method Q)with sulfonyl halide (such as methanesulfonyl chloride) in the presenceof a base.

Examples of the base used include triethylamine, diisopropylethylamine,pyridine, and 4-dimethylaminopyridine (DMAP).

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include methanol, ethanol,tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate,dichloromethane, chloroform, toluene and a mixture of these. Thereaction temperature is usually about 0 to 100° C. and the reaction timeis usually about 5 minutes to 24 hours.

(Step S2) Step of Etherification by Substitution Reaction

This is a step of producing the compound (S-III) by reacting thecompound (S-II) in a solvent with the corresponding alcohol in basicconditions.

Examples of the base used include sodium methylate, potassiumtert-butoxide, sodium hydride, potassium hydride, sodiumbistrimethylsilylamide, and lithium bistrimethylsilylamide.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include diethyl ether,tetrahydrofuran, toluene, hexane, N,N-dimethylformamide, dimethylsulfoxide and a mixture of these. The reaction temperature is usuallyabout 0 to 200° C. and the reaction time is usually about 5 minutes to24 hours.

[Method T]

Method T is a method of producing a compound (T-IV) of the presentinvention. In this method, for convenience, the case where the structurerepresented by G in the compound of the general formula (1) of thepresent invention is 1,2,4-triazole is described as an example. However,even when the structure represented by G is another 5-membered aromaticheterocyclic compound, the target compound can be produced in the samemanner by a method usually used in this field.

wherein the symbols used in the formula are as defined above. Lrepresents a leaving group.

(Step T1) Step of Oxidizing Alcohol to Form Aldehyde

This is a step of producing a compound (T-II) by reacting a compound(T-I) (equivalent to the compound (Q-VIII) that is used in Method Q)with an oxidizing agent in a solvent under the same conditions as inStep M5 of Method M.

(Step T2) Step of Increasing Carbon in Aldehyde to Form Enol Ether

This is a step of producing a compound (T-III) by reacting the compound(T-II) with a phosphonate compound (such as methyl triphenylphosphoniumbromide) in the presence of a base under the same conditions as in StepP1 of Method P.

(Step T3) Step of Conducting Addition Reaction

This is a step of producing a compound (T-IV) by reacting the compound(T-III) with the corresponding nucleophile (for example,3-(trifluoromethyl)-2-pyridone) in a solvent.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include tetrahydrofuran,1,4-dioxane, acetonitrile, toluene, hexane, N,N-dimethylformamide,dimethyl sulfoxide, and a mixture of these. The reaction temperature isusually about 0 to 200° C. and the reaction time is usually about 5minutes to 24 hours.

When the structure represented by J in the compound of the presentinvention is the following 1,3,4-oxadiazole:

the compound (U-VII) of the present invention can be produced, forexample, using the following Method U.

[Method U]

Method U is a method of producing the compound (U-VII) of the presentinvention. In this method, for convenience, the case where the structurerepresented by G in the compound of the general formula (1) of thepresent invention is 1,2,4-triazole is described as an example. However,even when the structure represented by G is another 5-membered aromaticheterocyclic compound, the target compound can be produced in the samemanner by a method usually used in this field.

wherein the symbols used in the formula are as defined above. P^(c)represents a carboxyl group-protecting group.

(Step U1) Step of Forming Oxadiazole Ring

This is a step of obtaining a compound (U-II) by reacting a compound(U-I) that is commercially available or can be synthesized by a knownmethod, with a dehydrating reagent (for example,(methoxycarbonylsulfamoyl) triethylammonium hydroxide inner salt(Burgess reagent)) in a solvent.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include tetrahydrofuran,1,4-dioxane, acetonitrile, toluene, N,N-dimethylformamide,dichloromethane and a mixture of these. The reaction temperature isusually about 0 to 150° C. and the reaction time is usually about 5minutes to 36 hours.

(Step U2) This is a step of obtaining a compound (U-III) by hydrolyzingthe compound (U-II) in a solvent in the presence of a base.

Examples of the base used include sodium hydroxide and lithiumhydroxide.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include tetrahydrofuran,methanol, water, and a mixture of these. The reaction temperature isusually about 0 to 150° C. and the reaction time is usually about 5minutes to 36 hours.

(Step U3) Step of Forming Amide by Condensation

This is a step of obtaining a compound (U-IV) from the compound (U-III)and a corresponding amine under the same conditions as in Step C1 ofMethod C.

(Step U4) Step of Thiocarbonylation

This is a step of obtaining a compound (U-V) by reacting the compound(U-IV) with a sulfurizing agent such as Lawesson's reagent in a solventunder the same conditions as in Step C2 of Method C.

(Step U5) Step of Forming Triazole Ring

This is a step of producing the compound (U-VII) by reacting thecompound (U-V) with an alkylating agent such as methyl iodide to convertit into the corresponding thioimidate, and reacting the thioimidate witha compound (U-VI) (equivalent to the compound (D-II) that is used inMethod D) under the same conditions as in Step B1 of Method B.

When the structure represented by J in the compound of the presentinvention is the following isoxazole:

the compound (V-IV) of the present invention can be produced, forexample, using the following Method V.

[Method V]

Method V is a method of producing the compound (V-IV) of the presentinvention. In this method, for convenience, the case where the structurerepresented by G in the compound of the general formula (1) of thepresent invention is 1,2,4-triazole is described as an example. However,even when the structure represented by G is another 5-membered aromaticheterocyclic compound, the target compound can be produced in the samemanner by a method usually used in this field.

wherein the symbols used in the formula are as defined above. V—IIrepresents a mixture of E and Z isomers.

(Step V1) Step to Forming Oxime

This is a step of producing a compound (V-II) by reacting the compound(V-I) (equivalent to the compound (M-VII) that is used in Method M) withhydroxylamine hydrochloride in the presence of a base.

Examples of the base used include triethylamine, pyridine, potassiumhydrogen carbonate, sodium hydrogen carbonate, potassium carbonate,sodium carbonate, cesium carbonate, potassium hydroxide, sodiumhydroxide, and sodium acetate.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include water, methanol,ethanol, tetrahydrofuran, N,N-dimethylformamide, toluene,dichloromethane, and a mixture of these. The reaction temperature isusually about 0 to 150° C. and the reaction time is usually about 0.5 to72 hours.

(Step V2) Step of Forming Isoxazole Ring by Cycloaddition Reaction

The is a step of producing the compound (V-IV) by reacting the compound(V-II) with N-chlorosuccinimide in the presence of a base, converting itinto the corresponding nitrile oxide, and subjecting the nitrile oxideto a cycloaddition reaction with a compound (V-III).

Examples of the base used include triethylamine, pyridine, potassiumhydrogen carbonate, sodium hydrogen carbonate, potassium carbonate,sodium carbonate, cesium carbonate, potassium hydroxide, and sodiumhydroxide.

The solvents used are not particularly limited as long as they do notinhibit the reaction, and examples thereof include water, methanol,ethanol, tetrahydrofuran, N,N-dimethylformamide, toluene,dichloromethane, chloroform, and a mixture of these. The reactiontemperature is usually about 0 to 100° C. and the reaction time isusually about 0.5 to 72 hours.

When the structure represented by J in the compound of the presentinvention is the following isoxazolidine:

the compound (W-III) of the present invention can be produced, forexample, using the following Method W.

[Method W]

Method W is a method of producing the compound (W-III) of the presentinvention. In this method, for convenience, the case where the structurerepresented by G in the compound of the general formula (1) of thepresent invention is 1,2,4-triazole is described as an example. However,even when the structure represented by G is another 5-membered aromaticheterocyclic compound, the target compound can be produced in the samemanner by a method usually used in this field.

wherein the symbols used in the formula are the same as defined above.W-I indicates a mixture of E and Z isomers.

(Step W1) Step of Forming Isoxazole Ring by Cycloaddition Reaction

This is a step of producing the compound (W-III) by reacting a compound(W-I) (equivalent to the compound (V-II) that is used in Method V) withN-chlorosuccinimide in the presence of a base to convert it into thecorresponding nitrile oxide, and subjecting the nitrile oxide to acycloaddition reaction with a compound (W-II) under the same conditionsas in Step V2 of Method V.

[Method X]

Method X is a method of producing a compound (X-II)(equivalent to acompound (A-IV) that is used in Method A, equivalent to a compound(E-VII) that is used in Method E, and equivalent to a compound (H-III)that is used in Method H).

wherein the symbols used in the formula are the same as defined above.

(Step X1) Step of Increasing Carbon in Aldehyde to Form Alkyne

This is a step of producing the compound (X-II) by reacting a compound(X-I) that is commercially available or can be synthesized by a knownmethod, with an a-diazophosphonate compound in the presence of a baseunder the same conditions as in Step M6 of Method M.

[Method Y]

Method Y is a method of producing a compound (Y-II) (equivalent to thecompound (M-IX) that is used in Method M).

wherein the symbols used in the formula are the same as defined above.

(Step Y1) Step of Converting Amino Group into Azide Group

This is a step of obtaining a compound (Y-II) from a compound (Y-I) thatis commercially available or can be synthesized by a known method, byconverting an amino group into an azide group under the same conditionsas in Step A2 of Method A.

The compounds produced by the above methods can be isolated and purifiedby a method known in the art, such as extraction, precipitation,distillation, chromatography, fractional recrystallization andrecrystallization.

If a compound or an intermediate has an asymmetric carbon, it hasoptical isomers. These optical isomers can be isolated and purified by aconventional method such as fractional recrystallization (saltfractionation) using recrystallization via an appropriate salt, andcolumn chromatography. For a method of fractionating an optical isomerfrom a racemic body, refer to the document: J. Jacques et al,“Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc.”.

(Dosage Form)

As an administration route, oral administration using a tablet, a pill,a capsule, a granule, a powder or a liquid; or parenteral administrationusing an injection such as intra-articular, intravenous or intramuscularinjections, a suppository, an eye drop, an eye ointment, a transdermalliquid, an ointment, a transdermal patch, a transmucosal liquid, atransmucosal patch or an inhalant, may be employed.

As a solid composition for oral administration, tablets, powders,granules or the like are used. In such a solid composition, one or twoor more active ingredients are mixed with at least one type of inactiveexcipient such as lactose, mannitol, dextrose, hydroxypropyl cellulose,microcrystalline cellulose, starch, polyvinylpyrrolidone and/ormagnesium aluminometasilicate. In such a solid composition, an inactiveadditive such as a lubricant (for example, magnesium stearate), adisintegrant such as sodium carboxymethyl starch, a stabilizer and/or asolubilizer, may be added in accordance with a conventional method.Tablets or pills, if necessary, may be coated with sugar or a filmsoluble in the stomach or intestine.

As a liquid composition for oral administration, a pharmaceuticallyacceptable emulsion, solution, suspension, syrup, elixir, or the likeare used. Such a liquid composition may contain an inactive diluent thatis generally used, such as purified water or ethanol. The liquidcomposition may contain an additive such as a solubilizer, a wettingagent, a sweetener, a flavor, an aroma material or an antiseptic agent,other than the inactive diluent.

As an injection for parenteral administration, an aqueous or non-aqueousaseptic solution, suspension, emulsion, or the like are used. Examplesof the aqueous solvent include distilled water for injection andphysiological saline. Examples of the non-aqueous solvent includepropylene glycol, polyethylene glycol, a vegetable oil such as oliveoil, an alcohol such as ethanol and Polysorbate 80. Such a compositionfor injection may further contain a tonicity agent, a preservative, awetting agent, an emulsifying agent, a dispersant, a stabilizer or asolubilizer. Such a composition for injection can be sterilized, forexample, by filtration through a sterilization filter, addition of adisinfectant or irradiation. Alternatively, such a composition forinjection can be produced as an aseptic solid composition, and dissolvedor suspended in aseptic water or aseptic solvent for injection justbefore use and then put in use.

As an external formulation, an ointment, a plaster, a cream, a jelly, acataplasm, a spray, a lotion, an eye drop, an eye ointment, and the likeare used. Such an external formulation contains an ointment base, alotion base, an aqueous or non-aqueous solution, a suspension, anemulsion, or the like that is generally used. Examples of the ointmentor lotion base include polyethylene glycol, propylene glycol, whitepetrolatum, beeswax, polyoxyethylene hydrogenated castor oil, glycerylmonostearate, stearyl alcohol, cetyl alcohol, lauromacrogol and sorbitansesquioleate.

As an inhalation and a transmucosal agent such as a transnasal agent, asolid, liquid or semi-solid composition is used and can be produced by amethod known in the art. Such an agent may appropriately contain, forexample, an excipient known in the art, further, a pH adjuster, apreservative, a surfactant, a lubricant, a stabilizer or a thickener.For these transmucosal agents, an appropriate device for inhalation orinsufflation can be used in the administration method. For example,using a device known in the art such as a metered dose inhalation deviceor a spray, a compound (of the invention) may be administered alone oras a composition, in the form of powder; or used in combination with apharmaceutically acceptable carrier in the form of a solution orsuspension. An inhaler such as a dry powder inhaler may be used forsingle administration or multiple administrations. A dry powder or apowder-containing capsule can be used. Alternatively, an appropriatepropellant can be used. For example, the inhaler may be a pressurizedaerosol spray using a suitable gas such as chlorofluoroalkane,hydrofluoroalkane or carbon dioxide.

(Dosage Amount)

In the case of oral administration, the proper dosage amount per day perweight is generally about 0.001-100 mg/kg, preferably 0.1-30 mg/kg, andmore preferably 0.1-10 mg/kg. This is administered in a single dose orin two or more doses. In the case of intravenous administration, theproper dosage amount per day per weight is about 0.0001-10 mg/kg andadministered in a single dose per day or in a plurality of doses. In thecase of a transmucosal agent, the dosage amount per weight is about0.001-100 mg/kg, which is administered in a single dose or in aplurality of doses. The dosage amount is appropriately and individuallydetermined in consideration of the symptoms, age and sex of theindividual.

(Combined Use)

In the present invention, the compound of the invention can be used incombination with various types of therapeutic agents or prophylacticagents expected to have an effect on a disease. The agent to be used incombination may be administered simultaneously or sequentially orintermittently at desired time intervals. The formulations to besimultaneously administered may be a combination drug or separate drugs.

(Formulation Example 1) Powdered Medicine

The compound of the present invention or a salt thereof (5 g), lactose(895 g) and corn starch (100 g) were mixed in a blender to obtain apowdered medicine.

(Formulation Example 2) Granule

The compound of the present invention or a salt thereof (5 g), lactose(865 g) and low substituted hydroxypropyl cellulose (100 g) were mixedand then a 10% aqueous solution of hydroxypropyl cellulose (300 g) wasadded thereto. The mixture was kneaded, granulated by an extrusiongranulator, and dried to obtain granules.

(Formulation Example 3) Tablet

The compound of the present invention or a salt thereof (5 g), lactose(90 g), corn starch (34 g), crystalline cellulose (20 g) and magnesiumstearate (1 g) were mixed in a blender and compressed into tablets by atableting machine to obtain tablets.

Pharmacological activity of the compound of the present invention or apharmacologically acceptable salt thereof was checked by the followingtest.

(Test Example) Measurement of IL-10 Increase Rate

A test substance was suspended in a 0.5% (w/v) methyl cellulose andorally administered to mice at a dose of 100 mg/kg. One hour later, alipopolysaccharide (LPS, Sigma-Aldrich, L2630 (trade name)) (0.4 mg/kg)was intraperitoneally administered to induce inflammation. One hourafter administration of LPS, blood was taken from the vena cava underanesthesia with isoflurane, placed in a tube containing a serumseparating agent, allowed to stand still at room temperature for 20-30minutes and centrifuged at 4° C. at 12,000 rpm for 5 minutes to obtainthe serum. Thereafter, the amount of the IL-10 in the serum was measuredby using Mouse IL-10 Quantikine ELISA Kit (R&D systems, M1000B (tradename)) or Mouse IL-10 Immunoassay kit (PerkinElmer, AL502 (trade name))in accordance with the protocol of the kit. The serum was diluted 10times with the dilution solution contained in the kit and put in use.IL-10 increase rate (% control ratio) of the compound was calculated inaccordance with the following expression:

IL-10 increase rate (% control ratio)=(IL-10 amount in compoundadministration group)×100/(IL-10 amount in 0.5% (w/v) methyl celluloseadministration group)

TABLE 1 IL10 Example Increase No. Rate (%) 1 146 2 220 3 179 4 131 5 2066 243 7 113 8 197 9 182 10 390 11 180 12 177 13 156 14 216 15 227 16 17017 334 18 157 19 227 20 176 21 312 22 113 23 232 24 257 25 216 26 231 27255 28 113 29 111 30 141 31 222 32 202 33 144 34 202 35 184 36 230

From this test result, it was shown that the compound of the presentinvention or a pharmacologically acceptable salt thereof is useful forpreventing and/or treating an inflammatory disease.

EXAMPLES

Now, the present invention will be more specifically described by way ofExamples. However, the present invention is not limited by these.

In the following Examples, nuclear magnetic resonance (hereinafterreferred to as ¹H NMR) spectra were obtained by using tetramethylsilaneas a standard substance and chemical shift values were expressed by δvalues (ppm). In a splitting pattern, a singlet was represented by s, adoublet d, a triplet t, a quartet q, a multiplet m and a broad br.

Example 11-Methyl-4-{1-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-1,2,3-triazol-4-yl}piperidine1a 2-[3-(Trifluoromethyl)phenoxy]acetohydrazide

Methyl 2-[3-(Trifluoromethyl)phenoxy]acetate (CAS Registry Number:588-26-1, WO2008078291) (3 g, 13 mmol) was dissolved in ethanol (15 mL).To this, hydrazine monohydrate (9.7 g, 192 mmol) was added, and themixture was stirred under heating to reflux for 8 hours.

After the reaction temperature had returned to room temperature, theresidue obtained by concentration under reduced pressure was purified bysilica gel column chromatography [elution solvent: methanol/ethylacetate] to obtain the title compound (1.2 g (yield: 40%)) as a whitesolid.

1b tert-Butyl N-[4-(methylcarbamothioyl)phenyl]carbamate

tert-Butyl N-[4-(methylcarbamoyl)phenyl]carbamate (CAS Registry Number:179625-42-4, WO1996013485) (1 g, 4 mmol) was dissolved intetrahydrofuran (20 mL). To this, Lawesson's reagent (1.8 g, 4.4 mmol)was added, and the mixture was stirred at room temperature for 4 hours.

To this, a 1N aqueous sodium hydroxide solution was added, and thereaction mixture was extracted with dichloromethane. The organic layerwas washed with saturated saline, and dried over anhydrous sodiumsulfate. The resultant was concentrated under reduced pressure andtriturated with diethyl ether to obtain the title compound (800 mg(yield: 80%)) as a yellowish white solid.

1c tert-ButylN-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]carbamate

The compound of Example 1(1b): tert-butylN-[4-(methylcarbamothioyl)phenyl]carbamate (200 mg, 0.75 mmol) wasdissolved in tetrahydrofuran (1 mL). To this, methyl iodide (0.93 mL, 15mmol) was added and the mixture was stirred at room temperature for 3hours.

The resultant was concentrated under reduced pressure, then the residuewas dissolved in ethanol (3 mL). To this, the compound of Example 1(1a):2-[3-(trifluoromethyl)phenoxy]acetohydrazide (352 mg, 1.5 mmol) wasadded, and the mixture was stirred at 100° C. for 6 hours.

After the reaction temperature had returned to room temperature,insoluble matters were filtered and concentrated under reduced pressure.The residue was triturated with dichloromethane to obtain the titlecompound (230 mg (yield: 68%)) as a yellowish white solid.

1d4-[4-Methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]aniline

The compound of Example 1(1c): tert-butylN-[4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]phenyl]carbamate(230 mg, 0.51 mmol) was dissolved in 2N hydrochloric acid-methanol (3mL) and the mixture was stirred at room temperature for 18 hours.

After the resultant was concentrated under reduced pressure, an aqueouspotassium carbonate solution was added, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline, and dried over anhydrous sodium sulfate. The driedproduct was concentrated under reduced pressure to obtain the titlecompound (170 mg (yield: 95%)) as a white solid.

1e3-(4-Azidophenyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole

The compound of Example 1(1d):4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]aniline(1.5 g, 4.3 mmol) was dissolved in acetonitrile (8.6 mL). To this,tert-butyl nitrite (1.3 g, 13 mmol) was added under ice-cooling, and themixture was stirred for 5 minutes. To the reaction solution,trimethylsilylazide (0.99 g, 8.6 mmol) was added, and the mixture wasstirred under ice-cooling for 10 minutes. To this, trifluoroacetic acid(0.49 g, 4.3 mmol) was then added, and the mixture was stirred at roomtemperature for 3.5 hours.

The resultant was concentrated under reduced pressure, and the resultantresidue was diluted with ethyl acetate. To the reaction mixture, waterwas added, and the reaction mixture was extracted with ethyl acetate.The organic layer was washed with saturated saline, and dried overanhydrous sodium sulfate. The resultant was concentrated under reducedpressure to obtain the title compound (303 mg (yield: 95%)) as a lightyellow solid.

1f tert-Butyl4-{1-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate

The compound of Example 1(1e):3-(4-azidophenyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole(500 mg, 0.975 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate(CAS Registry Number: 287192-97-6, WO2000044728) (0.031 g, 0.17 mmol)were dissolved in tetrahydrofuran (9.8 mL). To this,diisopropylethylamine (0.254 mL, 1.46 mmol) and copper (I) iodide (279mg, 1.47 mmol) were added, and the mixture was stirred at roomtemperature for 1 hour and allowed to stand still overnight.

To the reaction mixture, water was added, and the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried over anhydrous sodium sulfate. Theresidue obtained by concentration under reduced pressure was purified bysilica gel column chromatography [elution solvent: methanol/ethylacetate=0/1-1/9 (V/V)] to obtain the title compound (670 mg (yield:100%)) as a white solid.

1g4-{1-[4-(4-Methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-1,2,3-triazol-4-yl}piperidine

tert-Butyl4-{1-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylateof Example 1(1f) (0.57 g, 0.98 mmol) was dissolved in dichloromethane(3.9 mL). To this, trifluoroacetic acid (2.2 mL) was added, and themixture was stirred at room temperature for 2 hours.

To the residue obtained by concentration under reduced pressure,saturated aqueous sodium bicarbonate was added, and the mixture wasextracted with chloroform. The organic layer was washed with saturatedsaline, and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was triturated with ethyl acetateto obtain the title compound (120 mg (yield: 25%)) as a white solid.

1h1-Methyl-4-{1-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-1,2,3-triazol-4-yl}piperidine

The compound of Example 1(1g):4-{1-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-1,2,3-triazol-4-yl}piperidine(0.11 g, 0.23 mmol) was dissolved in dichloromethane (0.9 mL). To this,a formaldehyde solution (37%) (0.05 mL, 0.68 mmol) was added, and themixture was stirred at room temperature for 5 minutes. Then to thereaction mixture, sodium triacetoxyborohydride (95%) (0.24 g, 1.1 mmol)was added, and the mixture was stirred at room temperature for 1 hour.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the mixture was extracted with dichloromethane. The organic layerwas washed with saturated saline, and dried over anhydrous sodiumsulfate. To the residue obtained by concentration under reducedpressure, ethyl acetate was added, and the precipitated solid wascollected by filtration and then dried to obtain the title compound (86mg, yield: 53%)) as a light yellow solid.

Example 25-[4-(1-Methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl]-2-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)pyridine2a Methyl 2-(3-isopropylphenoxy)acetate

3-Isopropylphenol (Combi-Blocks Inc., Catalog Number: YF-6400) (10 g, 73mmol) was dissolved in N,N-dimethylformamide (100 mL). To this,potassium carbonate (20 g, 147 mmol) and methyl bromoacetate (TokyoChemical Industry Co., Ltd., Catalog Number: B0533) (7.4 mL, 81 mmol)were added, and the mixture was allowed to stand still at roomtemperature for 3 days.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with water and saturated salineand dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: hexane/ethyl acetate=1/0-7/3 (V/V)] toobtain the title compound (14.4 g (yield: 94%)) as a white solid.

2b 2-(3-Isopropylphenoxy)acetohydrazide

Methyl 2-(3-isopropylphenoxy) acetate (14.4 g, 69.1 mmol) from Example2(2a) was dissolved in ethanol (150 mL). To this, hydrazine monohydrate(10.4 g, 207 mmol) was added, and the mixture was stirred for 3 hours.

The reaction solution was concentrated to approximately half. To this,water (200 mL) was added, and the precipitated solid was collected byfiltration and washed with water. The resultant solid was dried toobtain the title compound (12.6 g (yield: 63%)) as a white solid.

2c tert-Butyl N-[6-(methylcarbamoyl)-3-pyridyl]carbamate

Methyl 5-(tert-butoxycarbonylamino)pyridine-2-carboxylate (CAS RegistryNumber: 131052-40-9, WO2016033445) (0.9 g, 3.6 mmol) was dissolved in a40% methylamine-methanol solution (about 9.8 mol/L) (30 mL, 290 mmol)and the mixture was stirred at 80° C. for 3 hours.

After the reaction temperature had returned to room temperature, thesolid obtained by concentration under reduced pressure was washed with amixture solvent of ethyl acetate and hexane to obtain the title compound(600 mg (yield: 70%)) as a white solid.

2d tert-Butyl N-[6-(methylcarbamothioyl)-3-pyridyl]carbamate

The compound of Example 2(2c): tert-butylN-[6-(methylcarbamoyl)-3-pyridyl]carbamate (0.6 g, 2.4 mmol) wasdissolved in tetrahydrofuran (10 mL). To this, Lawesson's reagent (1.1g, 2.6 mmol) was added, and the mixture was allowed to stand still atroom temperature overnight. Further Lawesson's reagent (1.1 g, 2.6 mmol)was added and the mixture was allowed to stand still at room temperatureovernight. Further Lawesson's reagent (1.06 g, 2.6 mmol) was added, andthe mixture was allowed to stand still at room temperature for 4 days.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with water and saturated salineand dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: hexane/ethyl acetate=10/0-7/3 (V/V)] toobtain the title compound (480 mg (yield: 75%)) as a white solid.

2e tert-ButylN-[6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]-3-pyridyl]carbamate

The compound of Example 2(2d): tert-butylN-[6-(methylcarbamothioyl)-3-pyridyl]carbamate (1.7 g, 6.4 mmol) wasdissolved in tetrahydrofuran (40 mL). To this, methyl iodide (4 mL, 64mmol) and potassium carbonate (0.88 g, 6.4 mmol) were added and themixture was stirred at room temperature for 5 hours.

The crude product obtained by removing insoluble matters by filtrationand concentrating the mother liquid was dissolved in 1,4-dioxane (20mL). To this, the compound of Example 2(2b): 2-(3-isopropylphenoxy)acetohydrazide (1.5 g, 7.0 mmol) was added, and the mixture was stirredat 100° C. for 6 hours.

After the reaction temperature had returned to room temperature, theresidue obtained by concentration under reduced pressure was purified bysilica gel column chromatography [elution solvent: hexane/ethylacetate=4/1-0/1 (V/V)] to obtain the title compound (360 mg (yield:13%)) as a light yellow solid.

2f6-[5-[(3-Isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]pyridin-3-amine

The compound of Example 2(2e): tert-butylN-[6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]-3-pyridyl]carbamate(0.36 g, 0.85 mmol) was dissolved in dichloromethane (4.5 mL). To this,trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred atroom temperature for 3 hours.

The reaction mixture was neutralized with saturated aqueous sodiumbicarbonate and extracted with dichloromethane. The organic layer waswashed with saturated saline, and dried over anhydrous sodium sulfate.The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent:methanol/ethyl acetate=0/1-1/20 (V/V)] to obtain the title compound (120mg (yield: 44%)) as a light yellow solid.

2g tert-Butyl4-{1-[6-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate

The compound of Example 2(2f):6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]pyridin-3-amine(0.3 g, 0.93 mmol) was dissolved in tetrahydrofuran (10 mL). To this,2-azido-1,3-dimethylimidazolinium hexafluorophosphate (0.52 g, 1.86mmol) and 4-dimethylaminopyridine (0.34 g, 2.8 mmol) were added and themixture was stirred at 50° C. for 7 hours.

The reaction mixture was poured into saturated aqueous sodiumbicarbonate and extracted with ethyl acetate. The organic layer waswashed with water and saturated saline and dried over anhydrous sodiumsulfate.5-Azido-2-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]pyridineobtained by concentration under reduced pressure (300 mg, 0.86 mmol) wasdissolved in tetrahydrofuran (9 mL). To this, copper (I) iodide (196 mg,1.03 mmol), N,N-diisopropylethylamine (0.22 mL, 1.3 mmol) and tert-butyl4-ethynylpiperidine-1-carboxylate (CAS Registry Number: 287192-97-6,WO2000044728) (216 mg, 1.03 mmol) were added, and the mixture wasallowed to stand still at room temperature overnight.

To the reaction mixture, saturated ammonium chloride water was added,and the reaction mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated saline and dried overanhydrous sodium sulfate. The solid obtained by concentration underreduced pressure was triturated with ethyl acetate and hexane to obtainthe title compound (165 mg (yield: 34%)) as a yellow solid.

2h2-(4-Methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)-5-[4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl]pyridine

The compound of Example 2(2g): tert-butyl4-{1-[6-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate(0.17 g, 0.30 mmol) was dissolved in dichloromethane (8 mL). To this,trifluoroacetic acid (2.0 mL, 26 mmol) was added, and the mixture wasstirred at room temperature for 3 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with dichloromethane. The organiclayer was washed with saturated saline, and dried over anhydrous sodiumsulfate. The residue obtained by concentration under reduced pressurewas purified by NH silica gel column chromatography [elution solvent:methanol/ethyl acetate=1/10-3/7 (V/V)] to obtain the title compound (121mg (yield: 89%)) as a yellow solid.

2i5-[4-(1-Methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl]-2-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)pyridine

The compound of Example 2(2h):2-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)-5-[4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl]pyridine(0.12 g, 0.26 mmol) was dissolved in ethanol (3 mL). To this, aformaldehyde solution (37%) (0.097 mL, 1.32 mmol), acetic acid (0.158 g,2.64 mmol) and sodium triacetoxyborohydride (0.17 g, 0.79 mmol) wereadded and the mixture was stirred at room temperature for 3 hours.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was washed with saturated saline, and driedover anhydrous sodium sulfate. The residue obtained by concentrationunder reduced pressure was purified by NH silica gel columnchromatography [elution solvent: methanol/ethyl acetate=0/1-1/9 (V/V)]to obtain the title compound (63 mg (yield: 50%)) as a yellow solid.

Example 34-Fluoro-1-methyl-4-{1-[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine3a tert-Butyl N-[trans-4-(methylcarbamothioyl)cyclohexyl]carbamate

tert-Butyl N-[trans-4-(methylcarbamoyl)cyclohexyl]carbamate (CASRegistry Number: 1013111-97-1, WO2015103453) (2.16 g, 8.26 mmol) wasdissolved in tetrahydrofuran (40 mL). To this, Lawesson's reagent (3.67g, 9.08 mmol) was added, and the mixture was stirred at 80° C. for 6hours.

After the reaction temperature had returned to room temperature, theresidue obtained by concentration under reduced pressure was purified bysilica gel column chromatography [elution solvent: hexane/ethylacetate=7/3-3/7 (V/V)] to obtain the title compound (1.54 g (yield:69%)) as a pale gray solid.

3b Methyltrans-4-(tert-butoxycarbonylamino)-N-methyl-cyclohexanecarboximidothioate

The compound of Example 3(3a): tert-butylN-[trans-4-(methylcarbamothioyl)cyclohexyl]carbamate (1.5 g, 5.7 mmol)was dissolved in tetrahydrofuran (30 mL). To this, potassium carbonate(1.6 g, 11 mmol) and methyl iodide (1.2 g, 8.5 mmol) were added, and themixture was stirred for 8 hours under reflux with heating.

After the reaction temperature had returned to room temperature, thereaction mixture was filtered and concentrated under reduced pressure toobtain the title compound (1.6 g (yield: 96%)) as a white solid.

3c tert-Butyl[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]carbamate

The compound of Example 3(3b): methyltrans-4-(tert-butoxycarbonylamino)-N-methyl-cyclohexanecarboximidothioate(0.2 g, 0.7 mmol) was dissolved in N,N-dimethylformamide (3 mL). Tothis, the compound of Example 2(2b): 2-(3-isopropylphenoxy)acetohydrazide (164 mg, 0.7 mmol) was added and the mixture was stirredat 110° C. for 8 hours.

After the reaction temperature had returned to room temperature, thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with water and saturated saline and driedover anhydrous magnesium sulfate. The residue obtained by concentrationunder reduced pressure was purified by silica gel column chromatography[elution solvent: hexane/ethyl acetate=1/1-0/1, ethylacetate/methanol=7/3 (V/V)] to obtain the title compound (216 mg (yield:68%)) as a white solid.

3dtrans-4-(4-Methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexanamine

The compound of Example 3(3c): tert-butyl[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]carbamate(216 mg, 0.48 mmol) was dissolved in dichloromethane (3 mL). To this,trifluoroacetic acid (3 mL, 39 mmol) was added, and the mixture wasstirred at room temperature for 27 hours.

The residue obtained by concentration under reduced pressure wasdissolved in methanol (5 mL) and desalted with Amberlyst A-26 (OH)(Sigma-Aldrich, Catalog Number: 542571). The eluate was filtered andthen concentrated under reduced pressure to obtain the title compound(160 mg (yield: 95%)) as a colorless oily substance.

3e3-(trans-4-Azidocyclohexyl)-4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazole

The compound of Example 3(3d):trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexanamine(0.31 g, 0.96 mmol) was dissolved in dichloromethane (8 mL). To this,triethylamine (0.66 ml, 4.8 mmol) and 2-azido-1,3-dimethylimidazoliniumhexafluorophosphate (0.33 g, 1.2 mmol) were added and the mixture wasstirred at room temperature for 1 hour.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the mixture was extracted with ethyl acetate. The combined organiclayer was dried over anhydrous magnesium sulfate. The residue obtainedby concentration under reduced pressure was purified by silica gelcolumn chromatography [elution solvent: ethyl acetate alone] to obtainthe title compound (304 mg (yield: 90%)) as a white solid.

3f tert-Butyl4-hydroxy-4-{1-[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate

The compound of Example 3(3e):3-(trans-4-azidocyclohexyl)-4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazole(0.5 g, 1.41 mmol) was dissolved in tetrahydrofuran (7 mL). To this,copper (I) iodide (381 mg, 1.69 mmol), N,N-diisopropylethylamine (0.37mL, 2.1 mmol) and tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate(CAS Registry Number: 275387-83-2, WO2000035908) (381 mg, 1.69 mmol)were added, and the mixture was stirred at room temperature for 24hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was purified by NH silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/1-3/7 (V/V)] to obtain the titlecompound (785 mg (yield: 96%)) as a white solid.

3g tert-Butyl4-fluoro-4-{1-[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate

The compound of Example 3(3f): tert-butyl4-hydroxy-4-{1-[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate(360 mg, 0.62 mmol) was dissolved in dichloromethane (15 mL). To this,bis(2-methoxyethyl)aminosulfur trifluoride (0.2 mL, 0.93 mmol) was addedunder ice-cooling, and the mixture was stirred for 2 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was addedunder ice-cooling, and the reaction mixture was extracted withdichloromethane. The organic layer was washed with saturated saline anddried over anhydrous magnesium sulfate. The residue obtained byconcentration under reduced pressure was purified by NH silica gelcolumn chromatography [elution solvent: ethyl acetate/hexane=9/1, ethylacetate alone, ethyl acetate/methanol=9/1 (V/V)] to obtain the titlecompound (191 mg (yield: 53%)) as a white solid.

3h4-Fluoro-1-methyl-4-{1-[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine

The compound of Example 3(3g): tert-butyl4-fluoro-4-{1-[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate(0.55 g, 0.95 mmol) was dissolved in dichloromethane (10 mL). To this,trifluoroacetic acid (3 mL) was added, and the mixture was stirred atroom temperature for 3 hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was dissolved in tetrahydrofuran (2 mL). To this, aformaldehyde solution (37%) (0.36 mL, 4.9 mmol), acetic acid (0.29 g,4.9 mmol) and sodium triacetoxyborohydride (0.62 g, 2.9 mmol) were addedat room temperature, and the mixture was stirred for 18 hours.

The residue obtained by concentrating the reaction mixture was purifiedby NH silica gel column chromatography [elution solvent: methanol/ethylacetate=0/1-1/4 (V/V)] to obtain the title compound (320 mg (yield:66%)) as a white solid.

Example 44-Fluoro-1-methyl-4-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine4a (2R)-2-[3-(Propan-2-yl)phenoxy]propanehydrazide

Methyl (2R)-2-[(3-(propan-2-yl)phenoxy]propanoate (CAS Registry Number:1704955-34-9, (commercially available) Aurora Fine Chemicals LLC,Catalog Number: A27.074.107) (4.19 g, 18.9 mmol) was dissolved inethanol (50 mL). To this, hydrazine monohydrate (5 mL, 103 mmol) wasadded and the mixture was stirred for 2.5 hours.

To the residue obtained by concentrating the reaction mixture,dichloromethane and water were added, and the mixture was extracted withdichloromethane. The organic layer was washed with water and dried overanhydrous magnesium sulfate. The resultant was concentrated underreduced pressure to obtain the title compound (4.25 g (yield: 100%)) asa colorless oil.

4b tert-Butyl[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]carbamate

The compound of Example 3(3b): methyltrans-4-(tert-butoxycarbonylamino)-N-methyl-cyclohexanecarboximidothioate(4.25 g, 19.1 mmol) was dissolved in ethanol (50 mL). To this, thecompound of Example 4(4a): (2R)-2-[3-(propan-2-yl)phenoxy] propanehydrazide (4.25 g, 19.1 mmol) was added, and the mixture was stirred at100° C. for 4 hours.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent:hexane/ethyl acetate=1/1-0/1, ethyl acetate alone, ethylacetate/methanol=9/1 (V/V)]] to obtain the title compound (6.05 g(yield: 72%)) as a white solid.

4ctrans-4-(4-Methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexanamine

The compound of Example 4(4b): tert-butyl[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]carbamate(8.84 g, 20 mmol) was dissolved in dichloromethane (50 mL). To this,trifluoroacetic acid (10 mL, 131 mmol) was added, and the mixture wasstirred at room temperature for 3 hours.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent:methanol/ethyl acetate=0/1-3/2 (V/V)] to obtain the title compound (6.69g (yield: 98%)) as a white solid.

4d3-(trans-4-Azidocyclohexyl)-4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazole

The compound of Example 4(4c):trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexanamine(1.14 g, 3 mmol) was dissolved in acetonitrile (15 mL). To this,triethylamine (2.08 mL, 15 mmol) and 2-azido-1,3-dimethylimidazoliniumhexafluorophosphate (1.03 g, 3.59 mmol) were added, and the mixture wasstirred at room temperature for 2 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with ethyl acetate. The combinedorganic layer was dried over anhydrous magnesium sulfate. The residueobtained by concentration under reduced pressure was purified by NHsilica gel column chromatography [elution solvent: hexane/ethylacetate=7/3, ethyl acetate alone, ethyl acetate/methanol=9/1 (V/V)] toobtain the title compound (881 mg (yield: 80%)) as a white solid.

4e tert-Butyl4-hydroxy-4-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate

The compound of Example 4(4d):3-(trans-4-azidocyclohexyl)-4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazole(220 mg, 0.6 mmol) was dissolved in tetrahydrofuran (6 mL). To this,copper (I) iodide (136 mg, 0.72 mmol), N,N-diisopropylethylamine (0.16mL, 0.9 mmol) and tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate(CAS Registry Number: 275387-83-2, WO2000035908) (161 mg, 0.72 mmol)were added, and the mixture was stirred at room temperature overnight.

The residue obtained by concentrating the reaction mixture under reducedpressure was purified by NH silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/1-3/7 (V/V)] to obtain the titlecompound (353 mg (yield: 100%)) as a white solid.

4f tert-Butyl4-fluoro-4-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate

The compound of Example 4(4e): tert-butyl4-hydroxy-4-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate(6.38 g, 10.7 mmol) was dissolved in dichloromethane (100 mL). To this,bis (2-methoxyethyl) aminosulfate (3.46 mL, 16.1 mmol) was added at −50°C. and the mixture was stirred for 40 minutes while warming to 0° C.

To the reaction mixture, saturated aqueous sodium bicarbonate was addedunder ice-cooling, and the reaction mixture was extracted withdichloromethane. The organic layer was washed with saturated saline anddried over anhydrous magnesium sulfate. The residue obtained byconcentration under reduced pressure was purified by NH silica gelcolumn chromatography [elution solvent: hexane/ethyl acetate=9/1, ethylacetate alone, ethyl acetate/methanol=19/1 (V/V)]. To the obtained crudeproduct, ethyl acetate was added, and the precipitated solid wascollected by filtration to obtain the title compound (3.3 g (yield:52%=)) as a white solid.

4g4-Fluoro-1-methyl-4-(1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine

The compound of Example 4(4f): tert-butyl4-fluoro-4-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate(174 mg, 0.29 mmol) was dissolved in dichloromethane (3 mL). To this,trifluoroacetic acid (1 mL, 13 mmol) was added, and the mixture wasstirred at room temperature for 2 hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was dissolved in tetrahydrofuran (3 mL). To this, aformaldehyde solution (37%) (0.11 mL, 1.45 mmol), acetic acid (0.08 ml,4.9 mmol) and sodium triacetoxyborohydride (184 mg, 0.87 mmol) wereadded at room temperature and the mixture was stirred for 1 hour.

The residue obtained by concentrating the reaction mixture was purifiedby NH silica gel column chromatography [elution solvent: ethylacetate/methanol=1/0-4/1 (V/V)] to obtain the title compound (110 mg(yield: 74%)) as a white solid.

Example 54-{1-[trans-4-(5-{[4-Chloro-3-(trifluoromethyl)phenoxy]methyl}-4-methyl-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}-4-fluoro-1-methylpiperidine5a 2-{[tert-butyl(diphenyl)silyl]oxy}acetohydrazide

Methyl 2-{[tert-butyl(diphenyl)silyl]oxy}acetate (CAS Registry Number:154698-92-7, WO2015192817) (47.1 g, 129 mmol) was dissolved in ethanol(200 mL). To this, hydrazine monohydrate (61.9 g, 1.24 mol) was added,and the reaction mixture was stirred at room temperature for 30 minutes.

To the residue obtained by concentration under reduced pressure,dichloromethane and water were added, and the mixture was extracted withdichloromethane. The organic layer was dried over anhydrous magnesiumsulfate. The resultant was concentrated under reduced pressure to obtainthe title compound (46.3 g (Yield: 100%)) as a white solid.

5b tert-Butyl{trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}carbamate

The compound of Example 3(3b): methyltrans-4-(tert-butoxycarbonylamino)-N-methyl-cyclohexanecarboximidothioate(7.62 g, 26.6 mmol) was dissolved in ethanol (100 mL). To this, thecompound of Example 5(5a): 2-{[tert-butyl(diphenyl)silyl]oxy}acetohydrazide (8.74 g, 26.6 mmol) was added, andthe mixture was stirred at 80° C. for 1 hour.

After the reaction temperature had returned to room temperature, theresidue obtained by concentration under reduced pressure was purified bysilica gel column chromatography [elution solvent: hexane/ethylacetate=1/1-0/1, ethyl acetate/methanol=9/1 (V/V)] to obtain the titlecompound (5.74 g (yield: 39f)) as a white solid.

5c3-(trans-4-Azidocyclohexyl)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazole

The compound of Example 5(5b): tert-butyl{trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}carbamate(5.74 g, 10.5 mmol) was dissolved in dichloromethane (50 mL). To this,trifluoroacetic acid (10 ml, 131 mmol) was added under ice-cooling, andthe mixture was stirred at room temperature for 2 hours.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent: ethylacetate/methanol=1/0-2/3 (V/V)] to obtain the crude producttrans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexaneamine(5.73 g).

The obtained crude product was dissolved intrans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexanamine(5.73 g) in acetonitrile (50 mL). To this, triethylamine (7.26 mL, 52.4mmol) and 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (3.58 g,12.6 mmol) was added and the mixture was stirred at 50° C. for 2 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with ethyl acetate. The combinedorganic layer was dried over anhydrous magnesium sulfate. The residueobtained by concentration under reduced pressure was purified by NHsilica gel column chromatography [elution solvent: hexane/ethylacetate=4/1-0/1 (V/V)] to obtain the title compound (997 mg (yield:20%)) as a colorless oil.

5d4-(1-{trans-4-[5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-1,2,3-triazol-4-yl)-4-fluoropiperidine

tert-Butyl 4-ethynyl-4-fluoropiperidine-1-carboxylate (CAS RegistryNumber: 191327-86-3, WO1997018202) (1.0 g, 4.4 mmol) was dissolved indichloromethane (10 mL). To this, trifluoroacetic acid (3 mL, 39 mmol)was added under ice-cooling, and the mixture was stirred at roomtemperature for 2.5 hours.

The residue obtained by concentration under reduced pressure wasdissolved in tetrahydrofuran (10 mL). To this, the compound of Example5(5c)): 3-(trans-4-azidocyclohexyl)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazole (818 mg, 1.72mmol) and triethylamine (0.549 mL, 3.96 mmol) in Example 5(5c) wereadded, and then a solution oftris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (91 mg, 0.17 mmol) andtetrakis (acetonitrile) copper (I) hexafluorophosphate (64 mg, 0.17mmol) in a mixture of tetrahydrofuran (1 mL) and water (0.2 mL) wasadded at room temperature, and the mixture was stirred for 3 hours.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent:methanol/ethyl acetate=0/1-1/9 (V/V)] to obtain the title compound (297mg (yield: 29%)) as a light yellow solid.

5e4-(1-{trans-4-[5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-1,2,3-triazol-4-yl)-4-fluoro-1-methylpiperidine

The compound of Example 5(5d): 4-(1-{trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-1,2,3-triazol-4-yl)-4-fluoropiperidine(297 mg, 0.49 mmol) was dissolved in tetrahydrofuran (5 mL). To this, aformaldehyde solution (37%) (0.18 mL, 2.5 mmol) and sodiumtriacetoxyborohydride (314 mg, 1.48 mmol) were added at room temperatureand the mixture was stirred for 4 hours.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent: ethylacetate/methanol=1/0-4/1 (V/V)] to obtain the title compound (300 mg(yield: 98%)) as a colorless oil.

5f(5-{trans-4-[4-(4-Fluoro-1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}-4-methyl-4H-1,2,4-triazol-3-yl)methanol

The compound of Example 5(5e): 4-(1-{trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-1,2,3-triazol-4-yl)-4-fluoro-1-methylpiperidine(340 mg, 0.55 mmol) was dissolved in tetrahydrofuran (5 mL). To this,tetrabutylammonium fluoride (202 mg, 0.662 mmol) was added underice-cooling, and the mixture was stirred for 2.5 hours.

The residue obtained by concentration under reduced pressure waspurified by silica gel column chromatography [elution solvent: ethylacetate/methanol=I/O—4/1 (V/V)] to obtain the title compound (197 mg(yield: 66%)) as a light yellow oily substance.

5g4-{1-[trans-4-(5-{[4-Chloro-3-(trifluoromethyl)phenoxy]methyl}-4-methyl-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}-4-fluoro-1-methylpiperidine

The compound of Example 5(5f):(5-{trans-4-[4-(4-fluoro-1-methylpiperidin-4-yl)-1H-1,2,3-triazol-3-yl]cyclohexyl}-4-methyl-4H-1,2,4-triazol-3-yl)methanol(100 mg, 0.19 mmol) was dissolved in 1,4-dioxane (3 mL). To this,2-chloro-5-hydroxybenzotrifluoride (Tokyo Chemical Industry Co., Ltd.,Catalog Number: F0754) (780 mg, 5.7 mmol) and cyanomethylenetributylphosphorane (109 mg, 0.56 mmol) were added and the mixture wasstirred at 100° C. for 10 hours. To the reaction mixture, cyanomethylenetributylphosphorane (109 mg, 0.56 mmol) was added, and the mixture wasstirred at 100° C. for 6 hours. To the reaction mixture,N,N-dimethylformamide (1 mL) was added, and the mixture was stirred at100° C. for 20 hours.

After the reaction temperature had returned to room temperature, theresidue obtained by concentration under reduced pressure was purified byNH silica gel column chromatography [elution solvent: methanol/ethylacetate=0/1-3/7 (V/V)] to obtain the title compound (10 mg (yield: 10%))as a light yellow solid.

Example 64-{4-[(1R)-1-(Azetidin-1-yl)ethyl]phenyl}-1-[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazole6a Methyl 4-[(1R)-1-(azetidin-1-yl)ethyl]benzoate

(R)-Methyl 4-(1-aminoethyl)benzoate (CAS Registry Number: (912342-10-0,WO2011106632) (1.5 g, 8.4 mmol) was dissolved in acetonitrile (40 mL).To this, diisopropylethylamine (3.6 mL, 21 mmol), tetrabutylammoniumiodide (0.15 g, 0.42 mmol) and 1,3-dibromopropane (Tokyo ChemicalIndustry Co., Ltd., Catalog Number: D0202) (0.85 mL, 8.4 mmol) wereadded at room temperature, and the mixture was stirred at 100° C. for 9hours.

After the reaction temperature had returned to room temperature,saturated aqueous sodium bicarbonate was added to the reaction mixture,and the obtained reaction mixture was extracted with dichloromethane.The organic layer was dried over anhydrous magnesium sulfate. Theresidue obtained by concentration under reduced pressure was purified byNH silica gel column chromatography [elution solvent: hexane/ethylacetate=1/1-1/0 (V/V)] to obtain the title compound (1.65 g (yield:90%)) as a yellow oily substance.

6b {4-[(1R)-1-(Azetidin-1-yl)ethyl]phenyl}methanol

The compound of Example 6(6a): methyl4-[(1R)-1-(azetidin-1-yl)ethyl]benzoate (1.35 g, 6.16 mmol) wasdissolved in tetrahydrofuran (30 mL). To this, a lithium aluminiumhydride-tetrahydrofuran solution (2.5 M, 2.5 mL) was added underice-cooling, and the mixture was stirred at room temperature for 1 hour.

To the reaction mixture, water (0.25 mL), a 15% aqueous sodium hydroxidesolution (0.25 mL), and water (0.75 mL) were sequentially added, and themixture was stirred at room temperature for 10 minutes.

The reaction mixture was diluted with ethyl acetate, and filtered withcelite. The filtrate was concentrated under reduced pressure to obtainthe title compound (1.06 g (yield: 90%)) as a yellow oily substance.

6c 1-[(1R)-1-(4-Ethynylphenyl)ethyl]azetidine

The compound of Example 6(6b):{4-[(1R)-1-(azetidin-1-yl)ethyl]phenyl}methanol (1.06 g, 5.54 mmol) wasdissolved in 1,4-dioxane (25 mL), and manganese dioxide (IV) (723 mg,8.31 mmol) at room temperature, and the mixture was stirred at 80° C.for 2 hours. To the reaction mixture, manganese dioxide (IV) (723 mg,8.31 mmol) was added at room temperature, and the mixture was stirred at80° C. for 9 hours.

After the reaction temperature had returned to room temperature, thereaction mixture was filtered with celite. The filtrate was concentratedunder reduced pressure and the resultant residue was dissolved inmethanol (25 mL). To this, potassium carbonate (1.06 g, 11.1 mmol) anddimethyl(1-diazo-2-oxopropyl)phosphonate (0.83 mL, 5.54 mmol) were addedunder ice-cooling, and the mixture was stirred at room temperature for 3hours.

The reaction mixture was diluted with dichloromethane and water and thenextracted with dichloromethane. The organic layer was dried overanhydrous magnesium sulfate. The residue obtained by concentration underreduced pressure was purified by silica gel column chromatography[elution solvent: hexane/ethyl acetate=9/1-1/1 (V/V)] to obtain thetitle compound (740 mg (yield: 72%)) as a light yellow oily substance.

6d4-{4-[(1R)-1-(Azetidin-1-yl)ethyl]phenyl}-1-[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazole

The compound of Example 3(3e):3-(trans-4-azidocyclohexyl)-4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazole(50 mg, 0.14 mmol) was dissolved in tetrahydrofuran (3 mL). To this, thecompound of Example 6(6c): 1-[(1R)-1-(4-ethynylphenyl) ethyl]azetidine(31 mg, 0.17 mmol), N,N-diisopropylethylamine (0.074 mL, 0.42 mmol) andcopper(I) iodide (32 mg, 0.17 mmol) were added at room temperature, andthe mixture was stirred at room temperature for 24 hours.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent:methanol/ethyl acetate=0/1-1/4 (V/V)] to obtain the title compound (66mg (yield: 87%)) as a white solid.

Example 74-{4-[(1R)-1-(Azetidin-1-yl)ethyl]phenyl}-1-[4-(4-methyl-5-{(1S)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)bicyclo[2.2.2]oct-1-yl]-1H-1,2,3-triazole7a tert-Butyl [4-(methylcarbamoyl)bicyclo[2.2.2]oct-1-yl]carbamate

4-[(tert-Butoxycarbonyl)amino]bicyclo[2.2.2]octane-1-carboxylic acid(CAS Registry Number: (863304-76-1, WO2009152133) (2.00 g, 7.43 mmol)was dissolved in dichloromethane (20 mL). To this, methylaminehydrochloride (462 mg, 6.84 mmol), triethylamine (3.09 mL, 22.3 mmol)and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (3.39 g, 8.92 mmol) were added, and the mixture wasstirred at 30° C. for 15 hours.

The reaction mixture was diluted with dichloromethane and water, andthen extracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate. The residue obtained by concentration underreduced pressure was purified by silica gel column chromatography[elution solvent: methanol/dichloromethane=1/100-1/50 (V/V)] to obtainthe title compound (1.9 g (yield: 91%)) as a white solid.

7b tert-Butyl[4-(methylcarbamothioyl)bicyclo[2.2.2]oct-1-yl]carbamate

The compound of Example 7(7a): tert-Butyl[4-(methylcarbamoyl)bicyclo[2.2.2]oct-1-yl]carbamate (1.9 g, 6.73 mmol)was dissolved in tetrahydrofuran (20 mL). To this, Lawesson's reagent(2.86 g, 7.07 mmol) was added, and the mixture was stirred at 90° C. for12 hours.

The reaction mixture was diluted with water, and then extracted withethyl acetate. The organic layer was washed with saturated saline, anddried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: ethyl acetate/petroleum ether=1/10-1/1(V/V)] to obtain the title compound (1.4 g (yield: 70%)) as a whitesolid.

7c Methyl(2S)-2-[3-(propan-2-yl)phenoxy]propanoate

3-Isopropylphenol (20 g, 147 mmol) was dissolved in tetrahydrofuran (200mL). To this, methyl (2R)-2-hydroxypropanoate (CAS Registry Number:17392-83-5, Journal of Organic Chemistry (1987), 52(22), 4978-84) (15.3g, 147 mmol), triphenylphosphine (42.4 g, 162 mmol) and diethylazodicarboxylate (28.1 g, 162 mmol) were added under ice-cooling, andthe mixture was stirred at 50° C. for 15 hours.

To the reaction mixture, water was added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated saline,and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: ethyl acetate/petroleumether=1/500-1/100 (V/V)] to obtain the title compound (22 g (yield:67%)) as a white solid.

7d (2S)-2-[3-(Propan-2-yl)phenoxy]propanehydrazide

The compound of Example 7(7c): methyl(2S)-2-[3-(propan-2-yl)phenoxy]propanoate (22 g, 99 mmol) was dissolvedin ethanol (220 mL). To this, hydrazine monohydrate (19.8 g, 396 mmol)was added, and the mixture was stirred at 50° C. for 13 hours.

After the reaction temperature had returned to room temperature, themixture was concentrated under reduced pressure to obtain the titlecompound (16.9 g (yield: 77%)) as a colorless oily substance.

7e4-{4-[(1R)-1-(Azetidin-1-yl)ethyl]phenyl}-1-[4-(4-methyl-5-{(1S)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)bicyclo[2.2.2]oct-1-yl]-1H-1,2,3-triazole

The compound of Example 7(7b): tert-butyl[4-(methylcarbamothioyl)bicyclo[2.2.2]octa-1-yl]carbamate (900 mg, 3.02mmol) was dissolved in tetrahydrofuran (2 mL). To this, methyl iodide(3.38 mL, 54.4 mmol) and potassium carbonate (1.25 g, 9.06 mmol) wereadded and the mixture was stirred at 80° C. for 15 hours.

To the reaction mixture, water was added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated saline,and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was dissolved in tert-butanol (20mL). To this, the compound of Example 7(7d):(2S)-2-[3-(propan-2-yl)phenoxy] propane hydrazide (1.07 g, 4.80 mmol)was added and the mixture was stirred at 120° C. for 60 hours.

After the reaction temperature had returned to room temperature, theresidue obtained by concentration under reduced pressure was purified bysilica gel column chromatography [elution solvent:methanol/dichloromethane=1/100-1/40 (V/V)] to obtain tert-butyl[4-(4-methyl-5-{(1S)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)bicyclo[2.2.2]octa-1-yl]carbamateas a yellow oily substance.

The obtainedtert-butyl[4-(4-methyl-5-{(1S)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)bicyclo[2.2.2]octa-1-yl]carbamate(800 mg, 1.71 mmol) was dissolved in ethyl acetate (5 mL). To this, 4Nhydrochloric acid-ethyl acetate (2.14 mL, 8.56 mmol) was added underice-cooling and the mixture was stirred at 30° C. for 1 hour.

The residue obtained by concentration under reduced pressure wasdissolved in dichloromethane (5 mL). To this, triethylamine (1.37 mL,9.88 mmol) and 2-azido-1,3-dimethylimidazolinium hexafluorophosphate(676 mg, 2.37 mmol) were added, and the mixture was stirred at 50° C.for 12 hours.

To the reaction mixture, water was added, and the mixture was extractedwith dichloromethane. The organic layer was washed with saturatedsaline, and dried over anhydrous sodium sulfate. Of 800 mg of theresidue obtained by concentration under reduced pressure, 400 mg of theresidue was dissolved in tetrahydrofuran (5 mL). To this, copper (I)iodide (192 mg, 1.01 mmol), N,N-diisopropylethylamine (0.27 mL, 1.5mmol) and the compound of Example 6(6c):1-[(1R)-1-(4-ethynylphenyl)ethyl] azetidine (187 mg, 1.01 mmol) wereadded, and the mixture was stirred at 30° C. for 12 hours.

To the reaction mixture, water was added, and the mixture was extractedwith dichloromethane. The organic layer was washed with saturatedsaline, and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: methanol/dichloromethane=1/50-1/10(V/V)] to obtain the title compound (200 mg (yield: 24%)) as a yellowsolid.

Example 8(3R,6S)—N,N-Dimethyl-6-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}tetrahydro-2H-pyran-3-amine8a tert-Butyl[(3R,6S)-6-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}tetrahydro-2H-pyran-3-yl]carbamate

The compound of Example 4(4d):3-(trans-4-azidocyclohexyl)-4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazole(210 mg, 0.57 mmol) was dissolved in N,N-dimethylformamide (10 mL) andwater (1 mL). To this, tert-Butyl[(3R,6S)-6-ethynyltetrahydro-2H-pyran-3-yl]carbamate (CAS RegistryNumber: 881657-41-6, WO2006032466) (141 mg, 0.62 mmol), sodium ascorbate(45.5 mg, 0.23 mmol) and copper (II) sulfate pentahydrate (28 mg, 0.11mmol) were added, and the mixture was stirred at room temperature for 18hours.

To the reaction mixture, methanol was added, and the precipitated solidwas dissolved and ethyl acetate and saturated aqueous sodium bicarbonatewere added. The mixture was extracted with ethyl acetate. The organiclayer was washed with water, then with saturated saline, and then driedover anhydrous sodium sulfate. The residue obtained by concentrationunder reduced pressure was purified by silica gel column chromatography[elution solvent: hexane/ethyl acetate=3/2-0/1 (V/V), methanol/ethylacetate=1/3 (V/V)] to obtain the title compound (252 mg (yield: 74%)) asa white solid.

8b(3R,6S)—N,N-Dimethyl-6-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}tetrahydro-2H-pyran-3-amine

The compound of Example 8(8a): tert-butyl[(3R,6S)-6-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}tetrahydro-2H-pyran-3-yl]carbamate(249 mg, 0.42 mmol) was dissolved in methanol (4 mL). To this, 4Nhydrochloric acid-1,4-dioxane (8 mL, 32 mmol) was added and the mixturewas stirred at room temperature for 1 hour.

The residue obtained by concentrating the reaction mixture under reducedpressure was purified by NH silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/1-1/1 (V/V)]. To the obtained crudeproduct, acetonitrile was added, and the precipitated solid wascollected by filtration to obtain(3R,6S)-6-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}tetrahydro-2H-pyran-3-amine(179 mg) as a white solid.

The obtained(3R,6S)-6-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}tetrahydro-2H-pyran-3-amine(83 mg, 0.17 mmol) was dissolved in dichloromethane (8 mL). To this, aformaldehyde solution (37%) (0.28 mL, 3.7 mmol), acetic acid (0.06 mL,3.7 mmol) and sodium triacetoxyborohydride (760 mg, 3.6 mmol) were addedat room temperature and the mixture was stirred for 2 hours.

To the reaction mixture, methanol, dichloromethane and saturated aqueoussodium bicarbonate were added, and the mixture was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate. The residue obtained by concentration under reduced pressurewas purified by NH silica gel column chromatography [elution solvent:hexane/ethyl acetate=3/2-1/0, methanol/ethyl acetate=15/85 (V/V)]. Tothe obtained crude product, acetonitrile was added, and the precipitatedsolid was collected by filtration to obtain the title compound (93 mg(yield: 46%)) as a white solid.

Example 9N,N-Dimethyl-1-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}-2-oxabicyclo[2.2.2]octan-4-amine9a tert-Butyl (1-ethynyl-2-oxabicyclo[2.2.2]oct-4-yl)carbamate

tert-Butyl (1-formyl-2-oxabicyclo[2.2.2]oct-4-yl)carbamate (PharmaBlock,Inc., Catalog Number: PBJL0125) (500 mg, 1.96 mmol) was dissolved inmethanol (7.8 mL). To this, potassium carbonate (541 mg, 3.92 mmol) anddimethyl (1-diazo-2-oxopropyl)phosphonate (0.35 mL, 2.35 mmol) wereadded under ice-cooling, and the mixture was stirred at room temperaturefor 3 hours.

The reaction mixture was diluted with dichloromethane and water, andthen extracted with dichloromethane. The organic layer was washed with asaturated aqueous ammonium chloride solution and dried over anhydroussodium sulfate. To the residue obtained by concentration under reducedpressure, water was added, and the precipitated solid was collected byfiltration to obtain the title compound (474 mg (yield: 96%)) as a whitesolid.

9b tert-ButylN-[trans-4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]cyclohexyl]carbamate

The compound of Example 3(3b): methyltrans-4-(tert-butoxycarbonylamino)-N-methyl-cyclohexanecarboxyimidothioate (200 mg, 0.70 mmol) was dissolved inN,N-dimethylformamide (3 mL). To this, the compound of Example 1(1a):2-[3-(trifluoromethyl)phenoxy]acetohydrazide (164 mg, 0.70 mmol) ofExample 1 (1a) was added and the mixture was stirred at 110° C. for 8hours.

After the reaction temperature had returned to room temperature, thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with water and saturated saline and driedover anhydrous magnesium sulfate. The residue obtained by concentrationunder reduced pressure was purified by silica gel column chromatography[elution solvent: hexane/ethyl acetate=1/1-0/1, ethylacetate/methanol=7/3 (V/V)] to obtain the title compound (216 mg (yield:68%)) as a white solid.

9ctrans-4-[4-Methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]cyclohexanamine

The compound of Example 9(9b): tert-butylN-[trans-4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]cyclohexyl]carbamate(216 mg, 0.48 mmol) was dissolved in dichloromethane (3 mL). To this,trifluoroacetic acid (3 mL, 39 mmol) was added, and the mixture wasstirred at room temperature for 2⁷ hours.

The residue obtained by concentration under reduced pressure wasdissolved in methanol (5 mL) and desalted with Amberlyst A-26 (OH)(Sigma-Aldrich, Catalog Number: 542571). The eluate was filtered andthen concentrated under reduced pressure to obtain the title compound(160 mg (yield: 95%)) as a colorless oily substance.

9d3-(trans-4-Azidocyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole

The compound of Example 9(9c):trans-4-[4-methyl-5-[[3-(trifluoromethyl)phenoxy]methyl]-1,2,4-triazol-3-yl]cyclohexaneamine(300 mg, 0.85 mmol) was dissolved in dichloromethane (8 mL). To this,triethylamine (0.59 mL, 4.2 mmol) and 2-azido-1,3-dimethylimidazoliniumhexafluorophosphate (0.29 g, 1 mmol) were added and the mixture wasstirred at 30° C. for 1 hour.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with dichloromethane. Thecombined organic layer was dried over anhydrous magnesium sulfate. Theresidue obtained by concentration under reduced pressure was purified byNH silica gel column chromatography [elution solvent: ethyl acetatealone] to obtain the title compound (283 mg (yield: 88%)) as a whitesolid.

9e tert-Butyl(1-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}-2-oxabicyclo[2.2.2]oct-4-yl)carbamate

The compound of Example 9(9d):3-(trans-4-azidocyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole(500 mg, 1.31 mmol) was dissolved in tetrahydrofuran (7 mL). To this,the compound of Example 9 (9a): tert-butyl (1-ethynyl-2-oxabicyclo[2.2.2] octa-4-yl) carbamate (363 mg, 1.45 mmol) was added, and then asolution of tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (140 mg,0.26 mmol) and tetrakis(acetonitrile)copper (I) hexafluorophosphate (98mg, 0.26 mmol) in tetrahydrofuran (1 mL) and water (0.2 mL) was added,and the mixture was stirred for 2 hours, and then allowed to stand stillfor 12 hours.

To the reaction mixture, methanol and dichloromethane were added, andthe reaction mixture was extracted with dichloromethane. The combinedorganic layer was washed with saturated aqueous sodium bicarbonate anddried over anhydrous sodium sulfate. To the residue obtained byconcentration under reduced pressure, ethyl acetate was added, and theprecipitated solid was collected by filtration to obtain the titlecompound (756 mg (yield: 91%)) as a white solid.

9fN,N-Dimethyl-1-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}-2-oxabicyclo[2.2.2]octan-4-amine

The compound of Example 9(9e): tert-butyl(1-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}-2-oxabicyclo[2.2.2]octa-4-yl)carbamate(750 mg, 1.19 mmol) was dissolved in dichloromethane (3 mL). To this,trifluoroacetic acid (0.91 mL, 11.9 mmol) was added, and the mixture wasstirred at room temperature for 3 hours.

After the mixture was concentrated under reduced pressure andazeotropically concentrated with toluene, the residue was dissolved indichloromethane (5 mL) and methanol (2 mL). To this, a formaldehydesolution (37%) (0.55 mL, 7.4 mmol) was added, and the mixture wasstirred at room temperature for 5 minutes. To the reaction mixture,sodium triacetoxyborohydride (2.1 g, 9.9 mmol) was added, and themixture was stirred at room temperature for 1 hour and allowed to standstill for 12 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with dichloromethane. The organiclayer was washed with saturated saline, and dried over anhydrous sodiumsulfate. The residue obtained by concentration under reduced pressurewas purified by NH silica gel column chromatography [elution solvent:methanol/dichloromethane=0/1-1/9 (V/V)]. To the obtained residue, ethylacetate and hexane were added, and the precipitated solid was collectedby filtration to obtain the title compound (320 mg (yield: 46%)) as awhite solid.

Example 104-[4-(Azetidin-1-ylmethyl)bicyclo[2.2.2]oct-1-yl]-1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazole10a Methyl 4-(azetidin-1-ylcarbonyl)bicyclo[2.2.2]octane-1-carboxylate

4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (CAS RegistryNumber:18720-35-9, WO2001034610) (3 g, 14.1 mmol) was dissolved inN,N-dimethylformamide (50 mL). To this, azetidine hydrochloride (1.22 g,13.0 mmol), triethylamine (5.88 ml, 42.4 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (6.45 g, 17.0 mmol) were added, and the mixture wasstirred at 30° C. for 15 hours.

The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure. The resultant residue was purified by highperformance liquid chromatography to obtain the title compound (2.3 g(yield: 65%)) as a white solid.

10b Azetidin-1-yl[4-(hydroxymethyl)bicyclo[2.2.2]oct-1-yl]methanone

Lithium aluminium hydride (453 mg, 11.9 mmol) was added totetrahydrofuran (30 mL). To this, a solution of the compound of Example10(10a): methyl4-(azetidin-1-ylcarbonyl)bicyclo[2.2.2]octane-1-carboxylate (1 g, 3.98mmol) in tetrahydrofuran (10 mL) was added, and the mixture was stirredat 30° C. for 30 minutes.

To the reaction mixture, water (1 mL), 15% aqueous sodium hydroxidesolution (1 mL), and water (1 mL) were sequentially added. The reactionmixture was filtered, and the filtrate was concentrated under reducedpressure to obtain the title compound (820 mg (yield: 99%)) as a lightyellow oily substance.

10c 4-(Azetidin-1-ylcarbonyl)bicyclo[2.2.2]octane-1-carbaldehyde

Dimethylsulfoxide (269 mg, 3.44 mmol) was dissolved in dichloromethane(5 mL). To this, a solution of oxalyl chloride (546 mg, 4.31 mmol) indichloromethane (5 mL) was added dropwise at −78° C., and the mixturewas stirred for 5 minutes. To the reaction mixture, a solution ofExample 10(10b): azetidin-1-yl [4-(hydroxymethyl)bicyclo[2.2.2]oct-1-yl]methanone (600 mg, 2.87 mmol) in dichloromethane (5 mL)was added dropwise and the mixture was stirred at −78° C. for 30minutes. To the reaction mixture, triethylamine (3 mL) was added, andthe mixture was stirred at the same temperature for 15 minutes, andgradually warmed to room temperature, and then stirred for 10 minutes.

The reaction mixture was diluted with dichloromethane. To this, waterwas added, and the mixture was extracted with dichloromethane. Theorganic layer was washed with water and dried over anhydrous sodiumsulfate. The resultant was concentrated under reduced pressure to obtainthe title compound (550 mg (yield: 71%)) as a light yellow oilysubstance.

10d Azetidin-1-yl(4-ethynylbicyclo[2.2.2]oct-1-yl)methanone

The compound of Example 10(10c):4-(azetidin-1-ylcarbonyl)bicyclo[2.2.2]octane-1-carbaldehyde (550 mg,2.65 mmol) was dissolved in methanol (15 ml). To this, potassiumcarbonate (1.10 g, 7.95 mmol) anddimethyl(1-diazo-2-oxopropyl)phosphonate (763 mg, 3.98 mmol) were addedand the mixture was stirred at room temperature for 1.5 hours.

To the reaction mixture, water (20 mL) was added, and the reactionmixture was extracted with dichloromethane. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: methanol/ethyl acetate=1/5 (V/V)] toobtain the title compound (280 mg (yield: 52%)) as a white solid.

10e4-[4-(Azetidin-1-ylmethyl)bicyclo[2.2.2]oct-1-yl]-1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazole

The compound of Example 10(10d):azetidin-1-yl(4-ethynylbicyclo[2.2.2]oct-1-yl]methanone (260 mg, 1.28mmol) and Example 9(9d):3-(trans-4-azidocyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole(486 mg, 1.28 mmol) were dissolved in tetrahydrofuran (5 mL) and water(5 mL). To this, sodium ascorbate (51 mg, 0.26 mmol) and copper (II)sulfate pentahydrate (32 mg, 0.13 mmol) were added and the mixture wasstirred at 60° C. for 15 hours.

To the reaction mixture, water (30 mL) was added, and the reactionmixture was extracted with dichloromethane. The organic layer was driedover anhydrous sodium sulfate. The residue obtained by concentrationunder reduced pressure was purified by silica gel column chromatography[elution solvent: methanol/dichloromethane=1/15 (V/V)] to obtain thetitle compound (321 mg (yield: 44%)) as a white solid.

Example 11N,N-Dimethyl-4-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}bicyclo[2.2.2]octan-1-amine

4-Ethynyl-N,N-dimethylbicyclo[2.2.2]octane-1-amine (CAS Registry Number:96454-76-1, J. Org. Chem. 1985, 50, 2551-2557) (100 mg, 0.56 mmol) wasdissolved in tetrahydrofuran (5 mL) and water (5 mL). To this, thecompound of Example 9(9d):3-(trans-4-azidocyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole(215 mg, 0.56 mmol), sodium ascorbate (11 mg, 0.56 mmol) and copper(II)sulfate pentahydrate (18 mg, 0.11 mmol) were added, and the mixture wasfurther stirred at 60° C. for 3 hours.

To the reaction mixture, water was added, and the mixture was extractedwith dichloromethane. The organic layer was washed with saturatedsaline, and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: methanol/dichloromethane=0/1-1/1 (V/V),0.14 ammonia water] to obtain the title compound (96 mg (yield: 30%)) asa yellow solid.

Example 12N,N-Dimethyl-3-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}bicyclo[1.1.1]pentan-1-amine

tert-Butyl (3-ethynylbicyclo[1.1.1]pent-1-yl)carbamate (CAS RegistryNumber:1638761-54-2, WO2015141616) (150 mg, 0.72 mmol) was dissolved intert-butanol (4 mL) and water (4 mL). To this, the compound of Example9(9d):3-(trans-4-azidocyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole(303 mg, 0.8 mmol), sodium ascorbate (29 mg, 0.15 mmol) and copper (II)sulfate pentahydrate (18 mg, 0.07 mmol) were added, and the mixture wasstirred at 60° C. for 24 hours.

The reaction mixture was extracted with ethyl acetate. The organic layerwas washed with saturated saline, and dried over anhydrous sodiumsulfate. The residue obtained by concentration under reduced pressurewas purified by thin layer silica gel chromatography [developingsolvent: methanol/dichloromethane=1/1 (V/V)] to obtain tert-butyl(3-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}bicyclo[1.1.1]pent-1-yl)carbamate(220 mg) as a white solid.

The obtained tert-butyl(3-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}bicyclo[1.1.1]pent-1-yl)carbamate(220 mg) was dissolved in ethyl acetate (2 mL). To this, 4N hydrochloricacid-ethyl acetate (2 mL, 8 mmol) was added under ice-cooling, and themixture was stirred at room temperature for 20 hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was dissolved in methanol (8 mL). To this, a formaldehydesolution (37%) (0.32 mL, 1.2 mmol), acetic acid (0.011 mL, 0.19 mmol)and sodium cyanoborohydride (95.9 mg, 1.53 mmol) were added at roomtemperature and the mixture was stirred for 2.5 hours.

To the reaction mixture, water was added, and the mixture was extractedwith dichloromethane. The organic layer was washed with saturatedsaline, and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: ethyl acetate/petroleum ether=1/50-1/10(V/V)] to obtain the title compound (157 mg (yield: 80%)) as a whitesolid.

Example 134-Fluoro-1-methyl-4-{1-[(3R,6S)-6-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)tetrahydro-2H-pyran-3-yl]-1H-1,2,3-triazol-4-yl}piperidine13a tert-ButylN-[(3R,6S)-6-(methylcarbamothioyl)tetrahydropyran-3-yl]carbamate

tert-Butyl N-[(3R,6S)-6-(methylcarbamoyl)tetrahydropyran-3-yl]carbamate(CAS Registry Number: 1398570-72-3, WO2012121361) (914 mg, 3.5 mmol) wasadded to tetrahydrofuran (20 mL). To this, Lawesson's reagent (1.6 g,3.9 mmol) was added, and the mixture was stirred at 80° C. for 15 hours.

After the reaction temperature had returned to room temperature, theresidue obtained by concentration under reduced pressure was purified bysilica gel column chromatography [elution solvent: hexane/ethylacetate=7/3-3/7 (V/V)] to obtain the title compound (580 mg (yield:59%)) as a white solid.

13b tert-ButylN-[(3R,6S)-6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]tetrahydropyran-3-yl]carbamate

The compound of Example 13(13a): tert-butylN-[(3R,6S)-6-(methylcarbamothioyl)tetrahydropyran-3-yl]carbamate (580mg, 2.1 mmol) was dissolved in tetrahydrofuran (15 mL). To this,potassium carbonate (351 mg, 2.5 mmol) and methyl iodide (600 mg, 4.2mmol) were added and the mixture was stirred for 23 hours under refluxwith heating.

After the reaction temperature had returned to room temperature, thereaction mixture was filtered and concentrated under reduced pressure.The resultant residue was dissolved in 1,4-dioxane (20 mL) and to thesolution 2-(3-isopropylphenoxy)acetohydrazide (441 mg, 2.1 mmol) wasadded, and the mixture was stirred at 110° C. for 30 minutes.

After cooling, the residue obtained by concentration under reducedpressure was purified by silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/1-1/9 (V/V)] to obtain the titlecompound (499 mg (yield: 63%)) as a colorless oily substance.

13c(3R,6S)-6-[5-[(3-Isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]tetrahydropyran-3-amine

The compound of Example 13(13b): tert-ButylN-[(3R,6S)-6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]tetrahydropyran-3-yl]carbamate(499 mg, 1.6 mmol) was dissolved in dichloromethane (5 mL). To this,trifluoroacetic acid (5 mL) was added, and the mixture was stirred atroom temperature for 1 hour.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent:methanol/ethyl acetate=0/1-4/6 (V/V)] to obtain the title compound (377mg (yield: 98)) as a colorless oil.

13d3-[(2S,5R)-5-Azidotetrahydro-2H-pyran-2-yl]-4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazole

The compound of Example 13(13c): (3R,6S)-6-[5-[(3-isopropylphenoxy)methyl]-4-methyl-1,2,4-triazol-3-yl]tetrahydropyran-3-amine(300 mg, 0.91 mmol) was dissolved in acetonitrile (50 mL). To this,triethylamine (0.63 mL, 4.5 mmol) and 2-azido-1,3-dimethylimidazoliniumhexafluorophosphate (0.31 g, 1.1 mmol) were added, and the mixture wasstirred at 50° C. for 2 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with ethyl acetate. The combinedorganic layer was dried over anhydrous sodium sulfate. The residueobtained by concentration under reduced pressure was purified by NHsilica gel column chromatography [elution solvent: methanol/ethylacetate=0/1-1/9 (V/V)] to obtain the title compound (295 mg (yield:91%)) as a colorless oil.

13e tert-Butyl4-fluoro-4-{1-[(3R,6S)-6-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)tetrahydro-2H-pyran-3-yl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate

The compound of Example 13(13d):3-[(2S,5R)-5-azidotetrahydro-2H-pyran-2-yl]-4-methyl-5-{[3-propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazole(200 mg, 0.56 mmol) was dissolved in tetrahydrofuran (7 mL). To this,tert-butyl 4-ethynyl-4-fluoropiperidine-1-carboxylate (CAS RegistryNumber: 191327-86-3, WO1997018202) (140 mg, 0.62 mmol) was added, then asolution of tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (59.6 mg,0.11 mmol) and tetrakis (acetonitrile) copper (I) hexafluorophosphate(41.8 mg, 0.11 mmol) in tetrahydrofuran (1 mL) and water (0.2 mL) wasadded, and the mixture was stirred for 2 hours, and allowed to standstill for 12 hours.

To the reaction mixture, methanol, dichloromethane and 1N hydrochloricacid were added, and the mixture was extracted with dichloromethane. Thecombined organic layer was washed with saturated aqueous sodiumbicarbonate and dried over anhydrous sodium sulfate. To the residueobtained by concentration under reduced pressure, ethyl acetate wasadded, and the precipitated solid was collected by filtration to obtainthe title compound (565 mg (yield: 100%)) as a white solid.

13f4-Fluoro-1-methyl-4-{1-[(3R,6S)-6-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)tetrahydro-2H-pyran-3-yl]-1H-1,2,3-triazol-4-yl}piperidine

The compound of Example 13(13e): tert-butyl4-fluoro-4-{1-[(3R,6S)-6-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)tetrahydro-2H-pyran-3-yl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate(400 mg, 0.55 mmol) was dissolved in dichloromethane (1.4 mL). To this,trifluoroacetic acid (0.42 mL, 5.48 mmol) was added and the mixture wasstirred at room temperature for 3 hours.

After the resultant was concentrated under reduced pressure andazeotropically concentrated with toluene, the residue was dissolved indichloromethane (2 mL) and methanol (2 mL). To this, a formaldehydesolution (37%) (0.2 mL, 2.7 mmol) was added, and the mixture was stirredat room temperature for 5 minutes. To the reaction mixture, sodiumtriacetoxyborohydride (698 mg, 3.29 mmol) was added, and the mixture wasstirred at room temperature for 2 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with dichloromethane. The organiclayer was washed with saturated saline, and dried over anhydrous sodiumsulfate. The residue obtained by concentration under reduced pressurewas purified by NH silica gel column chromatography [elution solvent:methanol/ethyl acetate=0/1-1/9 (V/V)] to obtain the title compound (15mg (yield: 5.5%)) as a white solid.

Example 143-{trans-4-[4-(4-Fluoro-1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}-8-[3-(propan-2-yl)benzyl]-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine14a 4-(4-Methoxybenzyl)-2-[3-(propan-2-yl)benzyl]morpholin-3-one

4-(4-methoxybenzyl)morpholin-3-one (CAS Registry Number: 570398-19-5,WO2003061652) (6 g, 27.1 mmol) was dissolved in tetrahydrofuran (100mL). To this, a lithium diisopropylamine-tetrahydrofuran solution (2M,17.6 ml) was added dropwise at −78° C. and the mixture was stirred for30 minutes. To this, 1-(bromomethyl)-3-isopropylbenzene (CAS RegistryNumber: 75369-42-5, J. Am. Chem. Soc. 2014, 136, 642-645) (7.51 g, 35.3mmol) was then added, and the mixture was stirred at 25° C. for 2.5hours.

To the reaction mixture, a saturated aqueous ammonium chloride solutionwas added, and the mixture was extracted with ethyl acetate. Thecombined organic layer was washed with saturated saline and dried overanhydrous sodium sulfate. The residue obtained by concentration underreduced pressure was purified by high performance liquid chromatographyto obtain the title compound (5 g (yield: 52%)) as a yellow solid.

14b 2-[3-(Propan-2-yl)benzyl]morpholin-3-one

To the compound of Example 14(14a)4-(4-methoxybenzyl)-2-[3-(propan-2-yl)benzyl]morpholin-3-one (5 g, 14.1mmol), trifluoroacetic acid (100 mL, 1.31 mol) was added, and themixture was stirred at 120° C. for 36 hours.

To the residue obtained by concentration under reduced pressure,saturated aqueous sodium bicarbonate was added, and the mixture wasextracted with dichloromethane. The organic layer was washed withsaturated saline, and dried over anhydrous sodium sulfate. The residueobtained by concentration under reduced pressure was purified by silicagel column chromatography [elution solvent: ethyl acetate/petroleumether=1/10-1/1 (V/V)] to obtain the title compound (3 g (yield: 91%)) asa colorless oil.

14c 2-[3-(Propan-2-yl)benzyl]morpholine-3-thione

The compound of Example 14(14b):2-[3-(propan-2-yl)benzyl]morpholin-3-one (3 g, 12.9 mmol) was dissolvedin toluene (30 mL). To this, Lawesson's reagent (3.12 g, 7.72 mmol) wasadded and the mixture was stirred at 90° C. for 12 hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was purified by silica gel column chromatography [elutionsolvent: ethyl acetate/petroleum ether=1/10-1/5 (V/V)] to obtain thetitle compound (1.7 g (yield: 53%)) as a white solid.

14d Methyl trans-4-azidocyclohexanecarboxylate

Methyl trans 4-aminocyclohexane carboxylate hydrochloride (CAS RegistryNumber: 61367-07-5, WO2003082847) (8 g, 41 mmol) was dissolved indichloromethane (100 mL). To this, triethylamine (28.6 mL, 207 mmol) and2-azido-1,3-dimethylimidazolinium hexafluorophosphate (13 g, 45.4 mmol)were added and the mixture was stirred at 50° C. for 12 hours.

To the reaction mixture, water was added, and the mixture was extractedwith dichloromethane. The organic layer was washed with saturatedsaline, and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: ethyl acetate/petroleum ether=1/10-1/5(V/V)]] to obtain the title compound (5 g (yield: 66%)) as a whitesolid.

14e tert-Butyl4-hydroxy-4-{1-[trans-4-(methoxycarbonyl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate

tert-Butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate (CAS RegistryNumber: 275387-83-2, WO2000035908) (7.38 g, 32.8 mmol) was dissolved intert-butanol (60 mL) and water (60 mL). The compound of Example 14(14d)methyl trans-4-azidocyclohexane carboxylate (5 g, 27.3 mmol), sodiumascorbate (541 mg, 2.73 mmol) and copper (II) sulfate pentahydrate (341mg, 1.36 mmol) were added, and the mixture was stirred at roomtemperature for 12 hours.

To the reaction mixture, water was added, and the mixture was extractedwith dichloromethane. The organic layer was washed with saturatedsaline, and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: ethyl acetate/petroleum ether=1/10-1/3(V/V)]] to obtain the title compound (10 g (yield: 90%)) as a yellowsolid.

14f tert-Butyl4-fluoro-4-{1-[trans-4-(methoxycarbonyl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate

The compound of Example 14(14e): tert-butyl4-hydroxy-4-{1-[trans-4-(methoxycarbonyl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate(10 g, 24.5 mmol) was dissolved in dichloromethane (80 mL). To this,(diethylamino)sulfur trifluoride (3.23 mL, 24.5 mmol) was added at −78°C. and the mixture was stirred at −78° C. for 1 hour, then warmed toroom temperature and stirred for 2 hours.

To the reaction mixture, water was added. The reaction mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous potassium carbonate solution and saturated saline anddried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by NH silica gelcolumn chromatography [elution solvent: ethyl acetate/petroleumether=1/5-1/1 (V/V)]] to obtain the title compound (7 g (yield: 70%)) asa yellow solid.

14g tert-Butyl4-fluoro-4-{1-[trans-4-(hydrazinylcarbonyl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate

The compound of Example 14(14f): tert-butyl4-fluoro-4-{1-[trans-4-(methoxycarbonyl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate(3 g, 7.31 mmol) was dissolved in ethanol (20 mL). To this, hydrazinemonohydrate (1.81 mL, 36.5 mmol) was added, and the mixture was stirredat 90° C. for 12 hours.

The solvent was mostly distilled off from the reaction mixture underreduced pressure, and the precipitated solid was collected by filtrationto obtain the title compound (2.8 g (yield: 93%)) as a white solid.

14h3-{trans-4-[4-(4-Fluoro-1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}-8-[3-(propan-2-yl)benzyl]-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazine

The compound of Example 14(14c):2-[3-(propan-2-yl)benzyl]morpholine-3-thione (800 mg, 3.2 mmol) wasdissolved in tetrahydrofuran (10 mL). To this, methyl iodide (1 mL, 16mmol) and potassium carbonate (0.67 g, 4.8 mmol) were added, and themixture was stirred at 90° C. for 3 hours.

Of 800 mg of the crude product obtained by removing insoluble matters byfiltration and concentrating the mother liquid, 400 mg of the crudeproduct was dissolved in isopropyl alcohol (10 mL) and the compound ofExample 14(14g): tert-butyl4-fluoro-4-{1-[trans-4-(hydrazinylcarbonyl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate(400 mg, 0.97 mmol) was added and the mixture was stirred at 90° C. for2 hours.

The reaction mixture was poured into water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate. Theresidue obtained by concentration under reduced pressure was purified bysilica gel column chromatography [elution solvent:methanol/dichloromethane=1/100-1/50 (V/V)] to obtain tert-butyl4-fluoro-4-[1-(trans-4-{8-[3-(propan-2-yl)benzyl]-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl}cyclohexyl)-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate(350 mg) as a yellow solid.

The obtained tert-butyl4-fluoro-4-[1-(trans-4-{8-[3-(propan-2-yl)benzyl]-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl}cyclohexyl)-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate(300 mg, 0.49 mmol) was dissolved in methanol (3 mL). To this, 4Nhydrochloric acid-methanol (1.2 mL, 4.8 mmol) was added, and the mixturewas stirred at room temperature for 2 hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was dissolved in methanol (10 mL). To this, a formaldehydesolution (37%) (0.12 mL, 1.7 mmol), triethylamine (0.21 mL, 1.5 mmol),acetic acid (0.09 ml, 1.5 mmol) and sodium cyanoborohydride (74 mg, 1.2mmol) were added, and the mixture was stirred at room temperature for 12hours.

The residue obtained by concentration under reduced pressure waspurified by high performance liquid chromatography to obtain the titlecompound (116 mg (yield: 22%)) as a white solid.

Example 153-{trans-4-[4-(4-Fluoro-1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}-8-[3-(trifluoromethyl)phenoxy]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine15a 3-[3-(Trifluoromethyl)phenoxy]piperidin-2-one

3-(Trifluoromethyl)phenol (CAS Registry Number: 98-17-9, WO2000053611)(640 mg, 3.95 mmol) was dissolved in tetrahydrofuran (15 mL). To this,3-hydroxypiperidin-2-one (CAS Registry Number: 19365-08-3, Journal ofOrganic Chemistry (1994), 59 (17), 5084-7) (500 mg, 4.34 mmol),triphenylphosphine (1.14 g, 4.34 mmol) and diethyl azodicarboxylate (756mg, 4.34 mmol) were added under ice-cooling, and the mixture was stirredat room temperature for 3 hours.

Water was added to the reaction mixture, and it was extracted with ethylacetate. The organic layer was washed with saturated saline, and driedover anhydrous sodium sulfate. The residue obtained by concentrationunder reduced pressure was purified by silica gel column chromatography[elution solvent: ethyl acetate/petroleum ether=1/1-1/2 (V/V)] to obtainthe title compound (0.72 g (yield: 70%)) as a colorless oily substance.

15b 3-[3-(Trifluoromethyl)phenoxy]piperidine-2-thione

The compound of Example 15(15a):3-[3-(trifluoromethyl)phenoxy]piperidin-2-one (700 mg, 2.7 mmol) wasdissolved in toluene (20 mL). To this, Lawesson's reagent (1.1 g, 2.7mmol) was added, and the mixture was stirred at 110° C. for 2 hours.

To the reaction mixture, water was added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated saline,and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: ethyl acetate/petroleum ether=1/10-1/2(V/V)]] to obtain the title compound (400 mg (yield: 54%)) as a whitesolid.

15c tert-Butyl4-fluoro-4-[1-(trans-4-{8-[3-(trifluoromethyl)phenoxy]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3-yl}cyclohexyl)-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate

The compound of Example 15(15b):3-[3-(trifluoromethyl)phenoxy]piperidine-2-thione (200 mg, 0.73 mmol)was dissolved in tetrahydrofuran (5 mL). To this, methyl iodide (0.45mL, 7.27 mmol) and potassium carbonate (0.30 g, 2.2 mmol) were added,and the mixture was stirred at 66° C. for 2 hours.

The residue obtained by concentration under reduced pressure was addedto a solution of the compound of Example 14(14g): tert-butyl4-fluoro-4-{1-[trans-4-(hydrazinylcarbonyl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine-1-carboxylate(500 mg, 1.2 mmol) and triethylamine (0.51 mL, 3.7 mmol) in isopropylalcohol (5 mL), and the mixture was stirred at 120° C. for 12 hours.

The residue obtained by concentration under reduced pressure waspurified by silica gel column chromatography [elution solvent:methanol/dichloromethane=1/100-1/60 (V/V)] to obtain the title compound(380 mg (yield: 49%)) as a white solid.

15d3-{trans-4-[4-(4-Fluoro-1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}-8-[3-(trifluoromethyl)phenoxy]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine

The compound of Example 15(15c): tert-butyl4-fluoro-4-[1-(trans-4-{8-[3-(trifluoromethyl)phenoxy]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3-yl}cyclohexyl)-1H-1,2,3-triazol-4-yl]piperidine-1-carboxylate(380 mg, 0.6 mmol) was dissolved in ethyl acetate (5 mL). To this, 4Nhydrochloric acid-ethyl acetate (0.75 mL, 3 mmol) was added, and themixture was stirred at 15° C. for 10 hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was dissolved in methanol (5 mL). To this, a formaldehydesolution (37%) (0.08 mL, 1.1 mmol), triethylamine (0.29 mL, 2.1 mmol),and acetic acid (0.06 ml, 1.1 mmol) were added and the mixture wasstirred at 15° C. for 30 minutes. To the reaction mixture, sodiumcyanoborohydride (88 mg, 1.4 mmol) was added, and the mixture wasstirred at 15° C. for 2.5 hours.

To the reaction mixture, water was added, and the mixture was extractedwith dichloromethane. The organic layer was washed with saturatedsaline, and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by high performanceliquid chromatography [developing solvent: ethyl acetate] to obtain thetitle compound (58 mg (yield: 15%)) as a yellow solid.

Example 161-Methyl-4-{1-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-pyrazol-4-yl}piperidine16a 4-Iodo-N-methylbenzenecarbothioamide

4-Iodo-N-methylbenzenamide (CAS Registry Number: 89976-43-2,WO2009016253) (21.3 g, 81.4 mmol) and Lawesson's reagent (34.6 g, 85.5mmol) were dissolved in toluene (400 mL) and the mixture was stirred at130° C. for 4 hours.

The reaction mixture was purified by NH silica gel column chromatography[elution solvent: dichloromethane alone]. The obtained crude product waswashed by adding hexane to obtain the title compound (21.8 g (yield:97%)) as a light yellow solid.

16b3-(4-Iodophenyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole

The compound of Example 16(16a): 4-iodo-N-methylbenzenecarbothioamide(21.8 g, 78.7 mmol) was dissolved in acetone (450 mL). To this, methyliodide (24.5 mL, 393 mmol) was added, and the mixture was stirred atroom temperature for 66.5 hours.

After the resultant was concentrated under reduced pressure andazeotropically concentrated with toluene, ethyl acetate and saturatedaqueous sodium bicarbonate were added to the residue, and the mixturewas extracted with ethyl acetate. The organic layer was washed with a10% aqueous sodium thiosulfate solution and saturated saline, and themixture was dried over anhydrous magnesium sulfate. The residue obtainedby concentration under reduced pressure was dissolved in ethanol (500mL), and 2-[3-(trifluoromethyl)phenoxy]acetohydrazide (12.3 g, 52.4mmol) of Example 1(1a) was added, and the mixture was stirred at 110° C.for 21 hours.

After the reaction temperature had returned to room temperature,diisopropyl ether was added to the residue obtained by concentrationunder reduced pressure, and the precipitated solid was collected byfiltration to obtain the title compound (23 g (yield: 95%)) as a whitesolid.

16c3-[4-(4-Bromo-1H-pyrazol-1-yl)phenyl]-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole

The compound of Example 16(16b):3-(4-iodophenyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole(1.04 g, 2.26 mmol), 4-bromo-1H-pyrazole (CAS Registry Number:2075-45-8, WO2003016275) (434 mg, 2.95 mmol) and potassium phosphate(1.44 g, 6.78 mmol) were dissolved in N,N-dimethylformamide (12 mL). Tothis, copper (I) iodide (110 mg, 0.58 mmol) was added, and the mixturewas stirred at 160° C. for 2 hours under a nitrogen atmosphere andmicrowave irradiation.

To the reaction mixture, concentrated ammonia water and water wereadded, and the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated saline and dried overanhydrous magnesium sulfate. The residue obtained by concentration underreduced pressure was purified by silica gel column chromatography[elution solvent: hexane/ethyl acetate=1/1-0/1, tetrahydrofuran/ethylacetate=2/3 (V/V)] to obtain the title compound (529 mg (yield: 49%)) asa light yellow solid.

16d1-Methyl-4-{1-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-pyrazol-4-yl}-1,2,3,6-tetrahydropyridine

The compound of Example 16(16c):3-[4-(4-bromo-1H-pyrazol-1-yl)phenyl]-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole(519 mg, 1.11 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1,2,3,6-tetrahydropyridine(CAS Registry Number: 1462950-11-2, US 20130261106) (574 mg, 2.21 mmol)and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride(72 mg, 0.11 mmol) were dissolved in 1,4-dioxane (20 mL). To this, a 2Naqueous sodium carbonate solution (2.21 mL, 4.42 mmol) was added, andthe mixture was stirred at 100° C. for 17 hours under a nitrogenatmosphere.

After the reaction temperature had returned to room temperature, thereaction mixture was extracted with ethyl acetate, then the organiclayer was washed with saturated saline and dried over anhydrous sodiumsulfate. The residue obtained by concentration under reduced pressurewas purified by polyethylenimine (PEI) silica gel column chromatography[elution solvent: tetrahydrofuran/ethyl acetate=1/1 (V/V)]. The obtainedcrude product was washed by adding isopropyl alcohol. The obtained crudeproduct was purified by diamine (DNH) silica gel column chromatography[elution solvent: hexane/ethyl acetate=7/3-0/1), tetrahydrofuran/ethylacetate=1/1 (V/V)]. To the obtained crude product, isopropyl alcohol wasadded, and the precipitated solid was collected by filtration to obtainthe title compound (361 mg (yield: 66%)) as an off-white solid.

16e1-Methyl-4-{1-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-pyrazol-4-yl}piperidine

The compound of Example 16(16d):1-methyl-4-{1-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-pyrazol-4-yl}-1,2,3,6-tetrahydropyridine(315 mg, 0.637 mmol) and 10% palladium on carbon catalyst (50 mg) wereadded to ethanol (12 mL), and the mixture was stirred at roomtemperature for 2 hours under a hydrogen atmosphere. Then thetemperature was raised to 70° C., and the mixture was stirred for 3hours.

The palladium-carbon was filtered off, and the filtrate was washed withethanol and concentrated under reduced pressure, and the resultantresidue was purified by high performance liquid chromatography. Afteracetonitrile was distilled off under reduced pressure, potassiumcarbonate was added to the resultant residue to adjust the pH to about8. Then, sodium chloride was added to saturate the aqueous solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated saline and dried over anhydrous magnesium sulfate.To the residue concentrated under reduced pressure, hexane/isopropylalcohol (1/1 (V/V)) was added, and the precipitated solid was collectedby filtration to obtain the title compound (223 mg (yield: 71%)) as alight yellow solid.

Example 173-(trans-4-{4-[trans-4-(Azetidin-1-yl)cyclohexyl]-1H-pyrazol-1-yl}cyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole17a Methyl trans-4-(4-bromo-1H-pyrazol-1-yl)cyclohexanecarboxylate

Methyl cis-4-[(methylsulfonyl)oxy]cyclohexane carboxylate (CAS RegistryNumber: 1959557-93-7, US 20160185785) (70 g, 296 mmol) was dissolved inN,N-dimethylformamide (12 mL). To this, 4-bromo-1H-pyrazole (CASRegistry Number: 2075-45-8, WO2003016275) (47.9 g, 326 mmol) andpotassium carbonate (81.9 g, 592 mmol) were added, and the mixture wasstirred at 80° C. for 16 hours.

To the reaction mixture, water was added, and the mixture was extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate. The residue obtained by concentration under reduced pressurewas purified by silica gel column chromatography [elution solvent: ethylacetate/petroleum ether=1/100-1/10 (V/V)]] to obtain the title compound(32 g (yield: 381)) as a white solid.

17b trans-4-(4-Bromo-1H-pyrazol-1-yl)cyclohexanecarbohydrazide

The compound of Example 17(17a): methyltrans-4-(4-bromo-1H-pyrazol-1-yl)cyclohexanecarboxylate (8 g, 27.9 mmol)was dissolved in ethanol (80 mL). To this, hydrazine monohydrate (14.2g, 279 mmol) was added and the mixture was stirred at 100° C. for 10hours.

After the reaction temperature had returned to room temperature, themixture was concentrated under reduced pressure, and the precipitatedsolid was collected by filtration to obtain the title compound (6.5 g(yield: 81%)) as a white solid.

17c N-Methyl-2-[3-(trifluoromethyl)phenoxy]ethanethioamide

N-Methyl-2-[3-(trifluoromethyl)phenoxy] acetamide (CAS Registry Number:87964-42-9, JP58134048) (300 g, 1.29 mol) was dissolved intetrahydrofuran (1.5 L). To this, Lawesson's reagent (313 g, 774 mmol)was added, and the mixture was stirred at 80° C. for 12 hours.

After the reaction temperature had returned to room temperature, theresidue obtained by concentration under reduced pressure was purified bysilica gel column chromatography [elution solvent: ethylacetate/petroleum ether=1/25-1/15 (V/V)] to obtain the title compound(220 g (yield: 68%)) as a white solid.

17d Methyl N-methyl-2-[3-(trifluoromethyl)phenoxy]ethanimidothioate

The compound of Example 17(17c):N-methyl-2-[3-(trifluoromethyl)phenoxy]ethanethioamide (210 g, 843 mmol)and potassium carbonate (233 g, 1.69 mol) were dissolved intetrahydrofuran (2 L). To this, methyl iodide (262 mL, 4.21 mol) wasadded, and the mixture was stirred at 80° C. for 12 hours.

The reaction mixture was filtered to remove insoluble matters, and thefiltrate was concentrated under reduced pressure to obtain the titlecompound (220 g (yield: 99%)) as a yellow oily substance.

17e3-[trans-4-(4-Bromo-1H-pyrazol-1-yl)cyclohexyl]-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole

The compound of Example 17(17b):trans-4-(4-bromo-1H-pyrazol-1-yl)cyclohexane carbohydrazide (6.5 g, 22.6mmol) was dissolved in isopropyl alcohol (100 mL). To this, the compoundof Example 17(17d): methylN-methyl-2-[3-(trifluoromethyl)phenoxy]ethanamidothioate (5.96 g, 22.6mmol) was added and the mixture was stirred at 100° C. for 20 hours.

The residue obtained by concentration under reduced pressure waspurified by silica gel column chromatography [elution solvent: ethylacetate/petroleum ether=1/20-1/1 (V/V)] to obtain the title compound (5g (yield: 46%)) as a white solid.

17f tert-Butyl(4-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohex-3-en-1-yl)carbamate

The compound of Example 17(17e):3-[trans-4-(4-bromo-1H-pyrazol-1-yl)cyclohexyl]-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole(2.50 g, 5.16 mmol),tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)cyclohex-3-en-1-yl)carbamate(CAS Registry Number: 1251732-64-5, WO2010118207) (2.50 g, 7.74 mmol)and cesium carbonate (5.05 g, 15.5 mmol) were dissolved in 1,4-dioxane(50 mL). To this, [1,1′-bis(diphenylphosphino)ferrocene] palladium (II)dichloride (302 mg, 0.41 mmol) was added at 10° C., and the mixture wasstirred at 120° C. for 12 hours under a nitrogen atmosphere.

To the reaction mixture, water was added. The reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated saline, and dried over anhydrous sodium sulfate. The residueobtained by concentration under reduced pressure was purified by silicagel column chromatography [elution solvent: tetrahydrofuran/ethylacetate=1/1 (V/V)]. The resulting crude product was washed by addingisopropyl alcohol. The resulting crude product was purified by diamine(DNH) silica gel column chromatography [elution solvent:methanol/dichloromethane=0/1-1/100 (V/V)] to obtain the title compound(2.1 g (yield: 681)) as a white solid.

17g tert-Butyl(trans-4-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)carbamate

10% palladium carbon catalyst (500 mg) was suspended in ethanol (100mL). To this, the compound of Example 17(17f): tert-butyl(4-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohex-3-en-1-yl)carbamate(2.1 g, 3.5 mmol) was added at 10° C., and the mixture was stirred at40° C. for 12 hours under a hydrogen atmosphere.

After purging with nitrogen, the palladium-carbon was filtered off. Theresidue obtained by concentration under reduced pressure was trituratedwith petroleum ether/ethyl acetate (10/1 (V/V)) to obtain the titlecompound (960 mg (yield: 46%)) as a white solid.

17h3-(trans-4-{4-[trans-4-(Azetidin-1-yl)cyclohexyl]-1H-pyrazol-1-yl}cyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole

The compound of Example 17(17g): tert-Butyl(trans-4-{1-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl) carbamate (860 mg, 1.43 mmol) was dissolved indichloromethane (5 mL). To this, 4N hydrochloric acid-ethyl acetate (5mL, 20 mmol) was added at 10° C. and the mixture was stirred at 10° C.for 2 hours.

The residue concentrated under reduced pressure was dissolved in ethanol(80 mL). To this, 1,3-dibromopropane (Tokyo Chemical Industry Co., Ltd.,Catalog Number: D0202) (270 mg, 1.34 mmol) and diisopropylethylamine(203 mg, 2.01 mmol) were added, and the mixture was stirred at 80° C.for 12 hours.

The residue obtained by concentration under reduced pressure waspurified by high performance liquid chromatography to obtain the titlecompound (110 mg (yield: 61%)) as a white solid.

Example 181-Methyl-4-{1-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-imidazol-4-yl}piperidine18aN,N-Dimethyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazole-1-sulfonamide

4-Iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide (CAS Registry Number:135773-25-0, WO2009023179) (234 mg, 0.78 mmol) was dissolved in1,4-dioxane (5 mL) and water (1 mL). To this,1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1,2,3,6-tetrahydropyridine(CAS Registry Number: 1462950-11-2, US 20130261106) (300 mg, 1.34 mmol),potassium carbonate (270 mg, 1.95 mmol) and bis(triphenylphosphine)palladium(II) dichloride (60 mg, 0.09 mmol) wereadded and the mixture was stirred at 130° C. for 30 minutes undermicrowave irradiation.

To the reaction mixture, ethyl acetate was added, then the mixture wasfiltered. The filtrate was washed with water, and the organic layer wasdried over anhydrous magnesium sulfate. The residue obtained byconcentration under reduced pressure was purified by NH silica gelcolumn chromatography [elution solvent: methanol/ethyl acetate=3/2-1/1(V/V)]. The resultant crude product was purified by silica gel columnchromatography [elution solvent: methanol/ethyl acetate=0/1-3/97,methanol/dichloromethane=1/9 (V/V)] to obtain the title compound (550 mg(yield: 62%)) as a white solid.

18b 4-(1H-Imidazol-4-yl)-1-methyl-1,2,3,6-tetrahydropyridinedihydrochloride

To the compound of Example 18(18a):N,N-dimethyl-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazole-1-sulfonamide(550 mg, 2.0 mmol), concentrated hydrochloric acid (excess amount) wasadded, and the mixture was stirred at 95° C. for 15 hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was washed by adding diethyl ether to obtain the title compound(500 mg (quantitative)) as a white solid.

18c 4-(1H-Imidazol-4-yl)-1-methylpiperidine dihydrochloride

The compound of Example 18(18b):4-(1H-imidazol-4-yl)-1-methyl-1,2,3,6-tetrahydropyridine hydrochloride(500 mg, 3.0 mmol) was dissolved in methanol (25 mL) and water (1 mL).To this, a 20% palladium hydroxide carbon catalyst (50 mg) was added andthe mixture was stirred under a hydrogen atmosphere at room temperaturefor 4 hours.

Palladium-carbon was filtered off and the filtrate was concentratedunder reduced pressure to obtain the title compound (460 mg(quantitative)) as a white solid.

18d1-Methyl-4-{1-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1H-imidazol-4-yl}piperidine

The compound of Example 18(18c): 4-(1H-imidazol-4-yl)-1-methylpiperidinehydrochloride (460 mg, 2.28 mmol), and the compound of Example 16(16b):3-(4-iodophenyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole(838 mg, 1.82 mmol) were dissolved in N,N-dimethylformamide (5 mL). Tothis, copper (I) iodide (173 mg, 0.91 mmol) and potassium phosphate (1.9g, 8.96 mmol) were added, and the mixture was stirred at 160° C. for 2hours under microwave irradiation, under a nitrogen atmosphere.

To the reaction mixture, ethyl acetate and water were added, and themixture was extracted with ethyl acetate. The residue obtained byconcentration under reduced pressure was purified by NH silica gelcolumn chromatography [elution solvent: methanol/ethyl acetate=0/1-5/95(V/V)] to obtain the title compound (100 mg (yield: 9%)) as a whitesolid.

Example 191,5-Anhydro-6-azetidin-1-yl-2,3,4,6-tetradeoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-1-yl}-D-erythro-hexitol19a Methyl trans-4-(methylcarbamoyl)cyclohexanecarboxylate

trans-4-(Methoxycarbonyl)cyclohexane carboxylic acid (Tokyo ChemicalIndustry Co., Ltd., Catalog Number: M2526) (25.3 g, 136 mmol) wasdissolved in dichloromethane (400 mL). To this, triethylamine (56.6 mL,408 mmol), methylamine hydrochloride (Tokyo Chemical Industry Co., Ltd.,Catalog Number: M0138) (18.4 g, 272 mmol),3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (0.93 g, 130 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29.5 g, 154mmol) were added and the mixture was stirred at room temperature for 70hours.

To the reaction mixture, water and 1N hydrochloric acid was added, andthe reaction mixture was extracted with dichloromethane. The organiclayer was dried over anhydrous magnesium sulfate. The resultant wasconcentrated under reduced pressure and the precipitated solid werediluted with hexane and the solid was collected by filtration to obtainthe title compound (25.7 g (yield: 95%)) as a white solid.

19b Methyl trans-4-(methylcarbamothioyl)cyclohexanecarboxylate

The compound of Example 19(19a): methyltrans-4-(methylcarbamoyl)cyclohexanecarboxylate (19 g, 95.5 mmol) wasdissolved in toluene (400 mL). To this, Lawesson's reagent (21.3 g, 52.5mmol) was added, and the mixture was stirred at 90° C. for 8 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with ethyl acetate. The organiclayer was washed with saturated saline and dried over anhydrousmagnesium sulfate. The residue obtained by concentration under reducedpressure was purified by NH silica gel column chromatography [elutionsolvent: dichloromethane/ethyl acetate=9/1-1/1 (V/V)] to obtain thetitle compound (20.6 g (yield: 100%)) as a white solid.

19c Methyltrans-4-[(methylimino)(methylsulfanyl)methyl]cyclohexanecarboxylate

The compound of Example 19(19b): methyltrans-4-(methylcarbamothioyl)cyclohexane carboxylate (1.5 g, 5.7 mmol)was dissolved in acetone (400 mL). To this, potassium carbonate (26.5 g,192 mmol) and methyl iodide (15.9 ml, 256 mmol) were added and themixture was stirred for 5 hours under reflux with heating.

After the reaction temperature had returned to room temperature,dichloromethane was added to the residue obtained by concentration underreduced pressure, and the precipitated solid was collected by filtrationto obtain the title compound 29.4 g (yield: 100%)) as a white solid.

19d Methyltrans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexanecarboxylate

The compound of Example 19(19c): methyltrans-4-[(methylimino)(methylsulfanyl)methyl]cyclohexanecarboxylate (0.2g, 0.7 mmol) was dissolved in ethanol (200 mL). The compound of Example1(1a): 2-[3-(trifluoromethyl)phenoxy]acetohydrazide (10.5 g, 44.9 mmol)was added and the mixture was stirred at 90° C. for 4 hours.

After the reaction temperature had returned to room temperature,dichloromethane and 1N hydrochloric acid were added to the residueobtained by concentration under reduced pressure. The mixture wasextracted with dichloromethane, and the organic layer was dried overanhydrous magnesium sulfate. The residue obtained by concentration underreduced pressure was dissolved in ethyl acetate. To this, hexane wasadded, and the precipitated solid was collected by filtration to obtainthe title compound (12.3 g (yield: 69%)) as a white solid.

19e[trans-4-(4-Methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]methanol

To a suspension of the compound of Example 19(19d) of methyltrans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexanecarboxylate(4.97 g, 12.5 mmol) in tetrahydrofuran (120 mL), a lithium aluminiumhydride-tetrahydrofuran solution (2.5 M, 7.5 mL) was added underice-cooling and the mixture was stirred at room temperature for 15minutes.

To the reaction mixture, water (0.33 mL), a 15% aqueous sodium hydroxidesolution (0.34 mL), and water (1 mL) were sequentially added underice-cooling, and the mixture was diluted with ethyl acetate and thenfiltered with celite. The filtrate was concentrated under reducedpressure to obtain the title compound (4.9 g (quantitative)) as a whitesolid.

19ftrans-4-(4-Methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexanecarbaldehyde

The compound of Example 19(19e):[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]methanol (4.9 g, 13.3 mmol) was dissolved in dichloromethane (130 mL).To this, Dess-Martin periodinane (6.75 g, 15.9 mmol) was added underice-cooling, and the mixture was stirred for 1 hour, and then thereaction temperature was raised to room temperature and the mixture wasstirred for 1 hour.

To the reaction solution, saturated aqueous sodium bicarbonate wasadded, and the mixture was extracted with dichloromethane. The combinedorganic layer was dried over magnesium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: hexane/ethyl acetate=1/1, ethyl acetatealone, methanol/ethyl acetate=1/4 (V/V)] to obtain the title compound(4.3 g (yield: 88%)) as a yellow oily substance.

19g3-(trans-4-Ethynylcyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole

The compound of Example 19(19f):trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexanecarbaldehyde(4.8 g, 13 mmol) was dissolved in methanol (100 mL). To this, potassiumcarbonate (3.5 g, 26 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate(3 g, 16 mmol) were added under ice-cooling, and the mixture was stirredat room temperature for 2 hours.

The reaction mixture was neutralized with 1N hydrochloric acid, and thenmethanol was distilled off under reduced pressure. The reaction mixturewas extracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate. The residue obtained by concentration underreduced pressure was purified by silica gel column chromatography[elution solvent: hexane/ethyl acetate=3/2-0/1 (V/V)] to obtain thetitle compound (4.5 g (yield: 93%)) as a white solid.

19h1,5-Anhydro-2-azido-6-O-[tert-butyl(dimethyl)silyl]-2,3,4-trideoxy-D-erythro-hexitol

2,6-Anhydro-1-O-[tert-butyl(dimethyl)silyl]-3,4-dideoxy-D-threo-hexitol(CAS Registry Number: 216098-97-4, Journal of Organic Chemistry (1998),63 (23), 8133-8144) (3.86 g, 15.7 mmol) was dissolved in pyridine (10mL). To this, para-toluenesulfonyl chloride (3.6 g, 18.8 mmol) and acatalytic amount of N,N-dimethyl-4-aminopyridine were added, and themixture was stirred at room temperature for 20 hours.

To the reaction mixture, water was added, and the reaction mixture wasstirred and extracted with ethyl acetate. The organic layer was washedwith water, saturated aqueous sodium bicarbonate and saturated salineand dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: hexane/ethyl acetate=9/1-1/1 (V/V)] toobtain2,6-anhydro-1-O-[tert-butyl(dimethyl)silyl]-3,4-dideoxy-5-O-[(4-methylphenyl)sulfonyl]-D-threo-hexitol(1.5 g) was obtained as a colorless oily substance.

The obtained2,6-anhydro-1-O-[tert-butyl(dimethyl)silyl]-3,4-dideoxy-5-O-[(4-methylphenyl)sulfonyl]-D-threo-hexitol(4.89 g, 12.2 mmol) was dissolved in N,N-dimethylformamide (80 mL). Tothis, sodium azide (2.49 g, 38.3 mmol) was added, and the mixture wasstirred at 80° C. for 1 hour. Then the reaction temperature was raisedto 100° C., and the mixture was stirred for 3 hours.

To the reaction mixture, 1N hydrochloric acid was added, and thereaction mixture was extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium bicarbonate and saturated salineand dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: hexane/ethyl acetate=3/2 (V/V)] toobtain the title compound (1.5 g (yield: 40%)) as a colorless oilysubstance.

19i1,5-Anhydro-6-O-[tert-butyl(dimethyl)silyl]-2,3,4-trideoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-1-yl}-D-erythro-hexitol

The compound of Example 19(19g):3-(trans-4-ethynylcyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole(2 g, 5.5 mmol) was dissolved in N,N-dimethylformamide (30 mL) and water(5 mL). To this, the compound of Example 19(19h):1,5-anhydro-2-azido-6-O-[tert-butyl(dimethyl)silyl]-2,3,4-trideoxy-D-erythro-hexitol(1.8 g, 6.1 mmol), sodium ascorbate (0.22 g, 1.1 mmol) and copper(II)sulfate pentahydrate (0.14 g, 0.55 mmol) were added and the mixture wasstirred at room temperature for 18 hours.

The reaction mixture was diluted with tetrahydrofuran and ethyl acetate,and neutralized with 1N hydrochloric acid. The reaction mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated saline and dried over anhydrous sodium sulfate. Theresidue obtained by concentration under reduced pressure was purified bysilica gel column chromatography [elution solvent: hexane/ethylacetate=7/3-0/1 (V/V)] to obtain the title compound (2.6 g (yield: 76%))as a white solid.

19j1,5-Anhydro-2,3,4-trideoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-1-yl}-D-erythro-hexitol

The compound of Example 19(19i): 1,5-anhydro-6-O-[tert-butyl(dimethyl)silyl]-2,3,4-trideoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-1-yl}-D-erythro-hexitol(2.6 g, 4.2 mmol) was dissolved in tetrahydrofuran (30 mL). To this, atetrabutylammonium fluoride-tetrahydrofuran solution (1 M, 6.3 mL) wasadded, and the mixture was stirred at room temperature for 1 hour.

To the reaction mixture, water and dichloromethane were added, and themixture was extracted with dichloromethane. The combined organic layerwas dried over sodium sulfate. The residue obtained by concentrationunder reduced pressure was purified by silica gel column chromatography[elution solvent: hexane/ethyl acetate=7/3-0/1, methanol/ethylacetate=25/75 (V/V)] to obtain the title compound (2.1 g (yield: 95%))as a white solid.

19k1,5-Anhydro-6-azetidin-1-yl-2,3,4,6-tetradeoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-1-yl}-D-erythro-hexitol

The compound of Example 19(19j):1,5-anhydro-2,3,4-trideoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-1-yl}-D-erythro-hexitol(1 g, 1.9 mmol) and lutidine (0.41 g, 3.9 mmol) were dissolved indichloromethane (25 mL). To this, trifluoromethanesulfonic anhydride(0.68 g, 2.4 mmol) was added dropwise at −78° C. The mixture was stirredat −78° C. for 1 hour, and then the temperature was raised to −40° C. Tothis, azetidine (1.1 g, 19 mmol) was added, and the mixture was stirredat −40° C. for 30 minutes. The mixture was stirred for 1 hour whilewarming to room temperature.

The residue obtained by concentration under reduced pressure waspurified by silica gel column chromatography [elution solvent:hexane/ethyl acetate=7/3-0/1, methanol/ethyl acetate=15/85 (V/V)] toobtain the title compound (0.61 g (yield: 571)) as a white solid.

Example 202-({5-[trans-4-(1-{trans-4-[3-(Fluoromethyl)azetidin-1-yl]cyclohexyl}-1H-1,2,3-triazol-4-yl)cyclohexyl]-4-methyl-4H-1,2,4-triazol-3-yl}methoxy)-4-(trifluoromethyl)pyridine20a Methyltrans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexanecarboxylate

The compound of Example 19(19c): methyl trans-4-[(methylimino)(methylsulfanyl)methyl]cyclohexanecarboxylate (18 g, 78.4 mmol) wasdissolved in ethanol (200 mL). To this, the compound of Example 5(5a):2-{[tert-butyl(diphenyl)silyl]oxy}acetohydrazide (25.7 g, 78.4 mmol) wasadded and the mixture was stirred at 90° C. for 16 hours.

After the reaction temperature had returned to room temperature, theresidue obtained by concentration under reduced pressure was dilutedwith dichloromethane. To this, 1N hydrochloric acid was added, and themixture was extracted with dichloromethane. The combined organic layerwas dried over magnesium sulfate. The residue obtained by concentrationunder reduced pressure was purified by silica gel column chromatography[elution solvent: hexane/ethyl acetate=1/1-0/1 (V/V), ethylacetate/methanol=9/1 (V/V)] to obtain the title compound (32 g (yield:83%)) as a colorless oily substance.

20b{trans-4-[5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}methanol

The compound of Example 20(20a): methyltrans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexanecarboxylate(24.9 g, 50.6 mmol) was dissolved in tetrahydrofuran (300 mL). To this,a lithium aluminium hydride-tetrahydrofuran solution (2.5 M, 20 mL) wasadded under ice-cooling, and the mixture was stirred for 5 minutes underice-cooling and then stirred at room temperature for 20 minutes.

To the reaction mixture, water (2 mL), a 15% aqueous sodium hydroxidesolution (2 mL), and water (6 mL) were sequentially added underice-cooling, and the mixture was diluted with ethyl acetate and thenfiltered with celite. The filtrate was concentrated under reducedpressure to obtain the title compound (23.4 g (yield: 99%)) as a whitesolid.

20ctrans-4-[5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexanecarbaldehyde

The compound of Example20(20b):{trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}methanol(18.8 g, 40.5 mmol) was dissolved in dichloromethane (250 mL). To this,Dess Martin periodinane (19 g, 44.6 mmol) was added under ice-cooling,and the mixture was stirred at room temperature for 1 hour.

To the reaction solution, a 1N aqueous sodium hydroxide solution (250mL) was added under ice-cooling and the mixture was stirred. To this,dichloromethane, and 10% aqueous sodium thiosulfate were further addedsequentially, and the mixture was filtered with celite. The reactionsolution was extracted with dichloromethane, and the organic layer wasdried over anhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure to obtain the title compound (19.5 g(quantitative)) as a light yellow solid.

20d 3-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-5-(trans-4-ethynylcyclohexyl)-4-methyl-4H-1,2,4-triazole

The compound of Example 20(20c): trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexanecarbaldehyde(5.03 g, 10.9 mmol) was dissolved in methanol (50 mL). To this,potassium carbonate (3.01 g, 21.8 mmol) anddimethyl(1-diazo-2-oxopropyl)phosphonate (1.64 mL, 10.9 mmol) were addedunder ice-cooling, and the mixture was stirred at room temperature for 1hour.

The reaction mixture was diluted with dichloromethane. To this, waterwas added, and the mixture was extracted with dichloromethane. Theorganic layer was dried over anhydrous sodium sulfate. The residueobtained by concentration under reduced pressure was purified by silicagel column chromatography [elution solvent: hexane/ethyl acetate=9/1-1/1(V/V)] to obtain the title compound (4.93 g (yield: 99%)) as a lightyellow oily substance.

20e[5-(trans-4-Ethynylcyclohexyl)-4-methyl-4H-1,2,4-triazol-3-yl]methanol

The compound of Example 20(20d): 3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-(trans-4-ethynylcyclohexyl)-4-methyl-4H-1,2,4-triazole(4.93 g, 10.8 mmol) was dissolved in tetrahydrofuran (50 mL). To this,tetrabutyl ammonium fluoride hydrate (3.61 g, 12.9 mmmol) was added andthe mixture was stirred at room temperature for 30 minutes.

To the reaction mixture, a saturated aqueous ammonium chloride solutionwas added, and the mixture was extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous ammonium chloride solution andsaturated saline and then dried over anhydrous magnesium sulfate. To theresidue obtained by concentration under reduced pressure, ethyl acetatewas added, and the precipitated solid was collected by filtration andwashed with ethyl acetate to obtain the title compound (504 mg (yield:21%)) as a white solid.

20f2-{[5-(trans-4-Ethynylcyclohexyl)-4-methyl-4H-1,2,4-triazol-3-yl]methoxy}-4-(trifluoromethyl)pyridine

To a suspension of the compound of Example 20(20e):[5-(trans-4-ethynylcyclohexyl)-4-methyl-4H-1,2,4-triazol-3-yl]methanol(504 mg, 2.30 mmol) in tetrahydrofuran (10 mL), sodium hydride (63%)(105 mg, 2.76 mmol) and 2-fluoro-4-(trifluoromethyl)pyridine (455 mg,2.76 mmol) were added under ice-cooling and the mixture was stirred at60° C. for 2 hours.

The reaction solution was ice-cooled, and a saturated aqueous ammoniumchloride solution was added, then the mixture was extracted withdichloromethane. The combined organic layer was dried over anhydrousmagnesium sulfate. The residue obtained by concentration under reducedpressure was purified by silica gel column chromatography [elutionsolvent: hexane/ethyl acetate=7/3, ethyl acetate alone, ethylacetate/methanol=9/1 (V/V)] to obtain the title compound (715 mg (yield:85%)) as a white solid.

20g tert-Butyl{trans-4-[3-(fluoromethyl)azetidin-1-yl]cyclohexyl}carbamate

2-(Fluoromethyl)propane-1,3-diol (CAS Registry Number: 1036393-01-7,WO2008078424) (6.06 g, 56.1 mmol) was dissolved in dichloromethane (400mL). To this, N,N-diisopropylethylamine (97.6 mL, 561 mmol) was added.Then, the mixture was cooled to −78° C. and trifluoromethanesulfonicacid anhydride (19.8 mL, 118 mmol) was added dropwise thereto, and themixture was stirred while warming to −20° C. To this, tert-butyl(trans-4-aminocyclohexyl) carbamate (Angene Chemical Private Limited,Catalog Number: AGN-PC-0O51A3) (12 g, 56.1 mmol) was added at −20° C.,and the mixture was stirred at room temperature for 7 hours.

To the reaction mixture, water was added, and the mixture was extractedwith dichloromethane. The combined organic layer was dried overmagnesium sulfate. The residue obtained by concentration under reducedpressure was dissolved in dichloromethane, then diluted with ethylacetate. The precipitated solid was filtered and washed with ethylacetate, and insoluble matters were filtered off. The residue obtainedby concentration under reduced pressure was purified by NH silica gelcolumn chromatography [elution solvent: [elution solvent: hexane/ethylacetate=7/3, ethyl acetate alone, methanol/ethyl acetate=9/1 (V/V)] toobtain the title compound (8.09 g (yield: 501)) as a light yellow solid.

20h trans-4-[3-(Fluoromethyl)azetidin-1-yl]cyclohexanaminedihydrochloride

The compound of Example 20(20g): tert-butyl {trans-4-[3-(fluoromethyl)azetidin-1-yl] cyclohexyl} carbamate (22.2 g, 77.5 mmol) was dissolvedin ethanol (100 mL). To this, 5N hydrochloric acid (200 mL) was added atroom temperature, and the mixture was stirred for 1 hour.

The residue obtained by concentrating the reaction solution underreduced pressure was dissolved in ethanol. To this, diethyl ether wasadded dropwise, and the resulting solid was collected by filtration toobtain the title compound (20 g (yield: 97%)) as a white solid.

20i2-({5-[trans-4-(1-{trans-4-[3-(Fluoromethyl)azetidin-1-yl]cyclohexyl}-1H-1,2,3-triazol-4-yl)cyclohexyl]-4-methyl-4H-1,2,4-triazol-3-yl}methoxy)-4-(trifluoromethyl)pyridine

Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (40.9 mg, 0.0772 mmol)and tetrakis(acetonitrile) copper (I) hexafluorophosphate (28.8 mg,0.0772 mmol) were dissolved in tetrahydrofuran (1 mL) and water (0.1 mL)to prepare a catalyst solution.

To a suspension of the compound of Example 20(20h):trans-4-[3-(fluoromethyl)azetidin-1-yl]cyclohexane amine hydrochloride(100 mg, 0.386 mmol) in acetonitrile (4 mL), N,N-diisopropylethylamine(0.47 mL, 2.7 mmol) and water (0.5 mL) were sequentially added. Upondissolution, 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (110mg, 0.39 mmol) was added at room temperature. The mixture was stirred atroom temperature for 1 hour, and then the compound of Example 20(20f):(2-{[5-(trans-4-ethynylcyclohexyl)-4-methyl-4H-1,2,4-triazol-3-yl]methoxy}-4-(trifluoromethyl)pyridine(169 mg, 0.46 mmol) and the aforementioned catalyst solution were addedat room temperature and the mixture was stirred for 24 hours.

The reaction mixture was purified by NH silica gel column chromatography[elution solvent: ethyl acetate alone, methanol/ethyl acetate=1/4 (V/V)]to obtain the title compound (168 mg (yield: 76%)) as a white solid.

Example 213-(trans-4-{1-[trans-4-(Azetidin-1-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole21a Ethyl4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohex-3-ene-1-carboxylate

Ethyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate(CAS Registry Number: 10490004-32-1, WO2008099221) (200 g, 714 mmol) and4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (CAS Registry Number:82099-98-7, WO2008092891) (150 g, 649 mmol) were dissolved in1,4-dioxane (900 mL). To this, [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (23.8 g, 32.5 mmol) and an aqueous cesiumcarbonate (423 g, 1.3 mol) solution (100 mL) were added at roomtemperature, and the mixture was stirred at 90° C. for 12 hours under anitrogen atmosphere.

The reaction solution was concentrated under reduced pressure, dilutedwith ethyl acetate, and then washed with saturated saline. The aqueouslayer was extracted with ethyl acetate, and then the combined organiclayer was dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: ethyl acetate/petroleum ether=1/20-1/15(V/V)] to obtain the title compound (160 g (yield: 81%)) as a yellowoily substance.

21btrans-4-[1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanecarbohydrazide

10% Palladium on carbon catalyst (24 g) was suspended in ethanol (1.5L). To this, the compound of Example 21(21a): ethyl4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohex-3-ene-1-carboxylate(160 g, 526 mmol) was added, and the mixture was stirred at roomtemperature for 12 hours under a hydrogen atmosphere.

After purging with nitrogen, the palladium-carbon was filtered off. Theresidue obtained by concentration under reduced pressure was dissolvedby adding tetrahydrofuran (1.5 L). To the obtained solution, sodiumhydride (60%) (41.8 g, 1.04 mol) was added under ice-cooling and themixture was stirred at 50° C. for 1.5 hours under a nitrogen atmosphere.

To the reaction solution, a saturated aqueous ammonium chloride solutionwas added, and the mixture was extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate. To the residue obtainedby concentration under reduced pressure, hydrazine monohydrate (500 g,9.79 mol) was added, and the mixture was stirred at 90° C. for 12 hours.

The residue obtained by concentration under reduced pressure waspurified by high performance liquid chromatography to obtain the titlecompound (45 g (yield: 391)) as a white solid.

21c4-Methyl-3-[trans-4-(1H-pyrazol-4-yl)cyclohexyl]-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole

The compound of Example 21(21b):trans-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexanecarbohydrazide (45 g, 154 mmol) was dissolved in isopropyl alcohol (500mL). To this, the compound of Example 17(17d): methylN-methyl-2-[3-(trifluoromethyl)phenoxy]ethaneimidothioate (60.8 g, 185mmol) was added, and the mixture was stirred at 100° C. for 36 hours.

The reaction mixture was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography[elution solvent: methanol/dichloromethane=1/100-1/50 (V/V)]. Theobtained residue was then dissolved in ethyl acetate (400 mL)-methanol(100 mL). To this, 4N hydrochloric acid-ethyl acetate (400 mL, 1.6 mol)was added at room temperature, and the mixture was stirred for 12 hours.

The residue obtained by concentrating the reaction mixture was dissolvedby adding dichloromethane and methanol, and washed with saturatedaqueous sodium bicarbonate, and the aqueous layer was extracted withdichloromethane. The combined organic layer was dried over anhydroussodium sulfate. The residue obtained by concentration under reducedpressure was triturated with ethyl acetate and petroleum ether to obtainthe title compound (30.5 g (yield: 92%)) as a white solid.

21d3-(trans-4-{1-[trans-4-(Azetidin-1-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole

cis-4-[(tert-Butoxycarbonyl) amino] cyclohexyl methanesulfonate (CASRegistry Number: 1007306-61-7, WO2011086053) (4.05 g, 21.1 mmol) and thecompound of Example 21(21c):4-methyl-3-[trans-4-(1H-pyrazol-4-yl)cyclohexyl]-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole(4 g, 9.87 mmol) were dissolved in N,N-dimethylformamide (20 mL). Tothis, sodium hydride (60%) (789 mg, 19.7 mmol) was added at roomtemperature, and the mixture was stirred at 50° C. for 12 hours.

To the reaction mixture, water was added, and the mixture was extractedwith dichloromethane. The organic layer was washed with saturatedsaline, and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: methanol/dichloromethane=1/60-1/20(V/V)]. The obtained tert-butyl(trans-4-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-1-yl}cyclohexyl)carbamate(850 mg) was dissolved by adding dichloromethane. To the obtainedsolution, 4N hydrochloric acid-ethyl acetate (10 mL, 40 mol) was addedat room temperature, and the mixture was stirred for 12 hours.

The reaction mixture was concentrated under reduced pressure, and theobtained residue was dissolved by adding acetonitrile (50 mL). To theobtained solution, 1,3-dibromopropane (1.7 mL, 16.7 mmol) andN,N-diisopropylethylamine (3.13 mL, 22.3 mmol)) were added at roomtemperature, and the mixture was stirred at 70° C. for 12 hours under anitrogen atmosphere.

The residue obtained by concentrating the reaction mixture under reducedpressure was purified by high performance liquid chromatography toobtain the title compound (600 mg (yield: 2.8%)) as a yellow solid.

Example 221,5-Anhydro-6-azetidin-1-yl-2,3,4,6-tetradeoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-1-yl}-D-erythro-hexitol22a1,5-Anhydro-2-[(tert-butoxycarbonyl)amino]-6-O-[tert-butyl(diphenyl)silyl]-2,3,4-trideoxy-D-erythro-hexitol

1,5-Anhydro-2-[(tert-butoxycarbonyl)amino]-2,3,4-trideoxy-D-erythro-hexitol(CAS Registry Number: 603130-12-7, WO2006125974) (3 g, 13.0 mmol) andimidazole (1.77 g, 25.9 mmol) were dissolved in N,N-dimethylformamide(25 mL). To this, tert-butyldiphenylchlorosilane (3.74 g, 13.6 mmol) wasadded dropwise at room temperature, and the mixture was stirred at roomtemperature for 55 hours.

To the reaction mixture, ethyl acetate and water were added, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated saline and dried over anhydrous magnesiumsulfate. The residue obtained by concentration under reduced pressurewas purified by silica gel column chromatography [elution solvent:hexane/ethyl acetate=19/1-7/3 (V/V)] to obtain the title compound (6.72g (yield: 100%)) as a colorless oily substance.

22b2-Amino-1,5-anhydro-6-O-[tert-butyl(diphenyl)silyl]-2,3,4-trideoxy-D-erythro-hexitol

The compound of Example 22(22a):1,5-anhydro-2-[(tert-butoxycarbonyl)amino]-6-O-[tert-butyl(diphenyl)silyl]-2,3,4-trideoxy-D-erythro-hexitol(6.72 g, 13 mmol) was dissolved in dichloromethane (30 mL). To this,trifluoroacetic acid (10 mL) was added under ice-cooling, and themixture was stirred for 30 minutes.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent: ethylacetate alone, ethyl acetate/methanol=4/1 (V/V)] to obtain the titlecompound (4.53 g (yield: 94%)) as a colorless oily substance.

22c1,5-Anhydro-2-[2-(tert-butoxycarbonyl)hydrazinyl]-6-O-[tert-butyl(diphenyl)silyl]-2,3,4-trideoxy-D-erythro-hexitol

The compound of Example 22(22b):2-amino-1,5-anhydro-6-O-[tert-butyl(diphenyl)silyl]-2,3,4-trideoxy-D-erythro-hexitol(2.49 g, 6.74 mmol) was dissolved in dichloromethane (60 mL). To this, asolution of tert-butyl 3-(trichloromethyl)oxadiridine-2-carboxylate (CASRegistry Number: 219547-77-0, WO2012074067) (1.15 g, 4.38 mmol) indichloromethane (5 mL) was added at −60° C. and the mixture was stirredfor 1 hour while warming.

The reaction temperature was raised to room temperature. The residueobtained by concentration under reduced pressure was purified by NHsilica gel column chromatography [elution solvent: hexane/ethylacetate=9/1, ethyl acetate alone, methanol/ethyl acetate=3/7 (V/V)] toobtain the title compound (1.72 g (yield: 81%)) as a colorless oilysubstance.

22d[trans-4-(4-Methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]acetaldehyde

To a suspension of (methoxymethyl)triphenylphosphonium chloride (3.38 g,9.85 mmol) in tetrahydrofuran (15 mL), tert-butoxypotassium (1.11 g,9.85 mmol) was added under ice-cooling, and the mixture was stirred for15 minutes. This solution was added dropwise using a cannula to asolution of the compound of Example 19(19f):trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexanecarbaldehyde(1.81 g, 4.93 mmol) in tetrahydrofuran (25 mL) under ice-cooling and themixture was stirred for 2 hours.

To the reaction mixture, water was added, and the mixture was extractedwith ethyl acetate. The organic layer was dried over anhydrous magnesiumsulfate. The residue obtained by concentration under reduced pressurewas dissolved by adding tetrahydrofuran (40 mL). To this, 1Nhydrochloric acid (10 mL) was added, and the mixture was stirred at roomtemperature for 30 minutes and then allowed to stand still for 13 hoursin a refrigerator.

The reaction mixture was concentrated, and diluted with ethyl acetate.To this, saturated aqueous sodium bicarbonate was added, and the mixturewas stirred for 10 minutes. The reaction mixture was extracted withethyl acetate, and the organic layer was washed with water and saturatedsaline and dried over anhydrous magnesium sulfate. The residue obtainedby concentration under reduced pressure was purified by silica gelcolumn chromatography [elution solvent: ethyl acetate alone,methanol/ethyl acetate=1/4 (V/V)] to obtain the title compound (1.32 g(yield: 71%)) as a colorless oily substance.

22e2-[trans-4-(4-Methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]prop-2-enal

The compound of Example 22(22d):trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]acetaldehyde(1.32 g, 3.46 mmol) was dissolved in N,N-dimethylformamide (7 mL). Tothis, formaldehyde solution (37%) (0.47 mL, 17.3 mmol) and L-proline(0.12 g, 1.04 mmol) were added, and the mixture was stirred at roomtemperature for 13 hours.

The reaction solution was diluted with ethyl acetate and washed withwater and saturated saline. The organic layer was dried over anhydrousmagnesium sulfate and then concentrated under reduced pressure to obtainthe title compound (1.35 g (yield: 99%)) as a white solid.

22f2-[trans-4-(4-Methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]oxirane-2-carbaldehyde

Sodium methoxide (0.196 mL, 3.43 mmol) was added to aqueous hydrogenperoxide (30%) (0.65 mL, 6.86 mmol), and the resulting suspension wasadded dropwise to a solution of the compound of Example 22(22e):2-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]prop-2-enal(1.32 g, 3.46 mmol) in methanol (15 mL) and the mixture was stirred atroom temperature for 10 minutes.

To the reaction mixture, a 10% aqueous sodium thiosulfate solution wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under reduced pressure to obtain the title compound (1.25 g(yield: 89%)) as a colorless oily substance.

22g1,5-Anhydro-2,3,4-trideoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-1-yl}-D-erythro-hexitol

The compound of Example 22(22c):1,5-anhydro-2-[2-tert-butoxycarbonyl)hydrazinyl]-6-O-[tert-butyl(diphenyl)silyl]-2,3,4-trideoxy-D-erythro-hexitol (1.72 g, 3.55 mmol)was dissolved in methanol (10 mL). To this, 5N hydrochloric acid (10 mL)was added, and the mixture was stirred at room temperature for 40minutes. Then, the reaction temperature was raised to 60° C., and themixture was stirred for 23 hours.

The reaction solution was concentrated, dissolved in methanol anddiluted with diethyl ether. The resulting precipitate was filtered andthe resulting solid was dissolved in methanol and concentrated again toobtain 1,5-anhydro-2,3,4-trideoxy-2-hydrazinyl-D-erythro-hexitolhydrochloride (658 mg) as a crude product.

The compound of Example 22(22f):2-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]oxirane-2-carbaldehyde(1.25 g, 3.05 mmol) was dissolved in ethanol (15 mL). To this, sodiumhydrogen carbonate (0.51 g, 6.1 mmol) was added at room temperature,then a solution of the above-mentioned crude product1,5-anhydro-2,3,4-trideoxy-2-hydrazinyl-D-erythro-hexitol hydrochloride(623 mg) in ethanol (5 mL) was added dropwise, and the mixture wasstirred at room temperature for 13 hours.

After the reaction mixture was diluted with dichloromethane, andinsoluble matters were filtered, and the filtrate was concentrated. Theresultant residue was purified by NH silica gel column chromatography[elution solvent: ethyl acetate alone, methanol/ethyl acetate=1/4 (V/V)]to obtain the title compound (1.41 g (yield: 89%)) as a white solid.

22h1,5-Anhydro-6-azetidin-1-yl-2,3,4,6-tetradeoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-1-yl}-D-erythro-hexitol

The compound of Example 22(22g):1,5-anhydro-2,3,4-trideoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-1-yl}-D-erytro-hexitol(100 mg, 0.19 mmol) was dissolved in dichloromethane (4 mL). To this,2,6-lutidine (0.0448 mL, 0.385 mmol) and trifluoromethanesulfonic acidanhydride (0.0388 mL, 0.231 mmol) were added at −30° C. and the mixturewas stirred for 45 minutes. To the reaction mixture, azetidine (44 mg,0.77 mmol) was added, and the mixture was stirred at 0° C. for 30minutes and at room temperature for 2 hours, and then stirred at 50° C.with heating under reflux.

After the reaction temperature had returned to room temperature, theresidue obtained by concentration under reduced pressure was purified byNH silica gel column chromatography [elution solvent: ethyl acetatealone, methanol/ethyl acetate=1/4 (V/V)] to obtain the title compound(49.7 mg (yield: 46%)) as a white solid.

Example 234-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]morpholine23a tert-Butyl2-[trans-4-(morpholin-4-yl)cyclohexyl]hydrazinecarboxylate

4-(Morpholin-4-yl)cyclohexanone (CAS Registry Number: 139025-93-7,WO2008095943) (6 g, 29.47 mmol) was dissolved in dichloroethane (40 mL).To this, acetic acid (0.51 mL, 8.84 mmol) and tert-butyl carbazate(Tokyo Chemical Industry Co., Ltd., Catalog Number: C0933) (4.01 g, 30.4mmol) were added, and the mixture was stirred at 10° C. for 1 hour, thensodium borohydride (4.99 g, 132 mmol) was added and the mixture wasstirred for 11 hours.

To the reaction solution, water was added, and the mixture was extractedwith dichloromethane. The combined organic layer was washed withsaturated saline and dried over anhydrous sodium sulfate. The residueobtained by concentration under reduced pressure was purified by silicagel column chromatography [elution solvent:dichloromethane/methanol=1/0-30/1, 0.11 ammonia water]. The obtainedresidue was purified by high performance liquid chromatography to obtainthe title compound (700 mg (yield: 7.9%)) as a white solid.

23b 4-(trans-4-Hydrazinylcyclohexyl)morpholine hydrochloride

The compound of Example 23(23a): tert-butyl2-[trans-4-(morpholin-4-yl)cyclohexyl]hydrazinecarboxylate (630 mg, 2mmol) was dissolved in dichloromethane (15 mL) To this, 4N Hydrochloricacid-ethyl acetate (2 mL, 8 mmol) was added, and the mixture was stirredat 10° C. for 10 hours.

The resultant mixture was concentrated under reduced pressure to obtainthe title compound (430 mg (yield: 89%)) as a white solid.

23c Methyl{[4-(trifluoromethyl)pyridin-2-yl]oxy}acetate

Methyl glycolate (Tokyo Chemical Industry Co., Ltd., Catalog Number:G0199) (87 g, 969 mmol) was dissolved in tetrahydrofuran (1.47 L). Tothis, sodium hydride (63%) (23.3 g, 969 mmol) and2-chloro-4-(trifluoromethyl)pyridine (Manchester, Catalog Number:S10181) were added at room temperature (80 g, 441 mmol) and the mixturewas stirred at 90° C. for 4 hours.

The reaction mixture was diluted with ethyl acetate and washed with asaturated aqueous ammonium chloride solution. The organic layer waswashed with saturated saline, and dried over anhydrous sodium sulfate.The residue obtained by concentration under reduced pressure waspurified by silica gel column chromatography [elution solvent:hexane/ethyl acetate=1/0-3/1 (V/V)] to obtain the title compound (88.2 g(yield: 85%)) as a colorless oily substance.

23d 2-{[4-(Trifluoromethyl)pyridin-2-yl]oxy}acetohydrazide

The compound of Example 23(23c):methyl{[4-(trifluoromethyl)pyridin-2-yl]oxy}acetate (111 g, 472 mmol)was dissolved in ethanol (2.4 L). To this, hydrazine monohydrate (177 g,3.54 mol) was added, and the mixture was stirred at 90° C. for 3 hours.

The resultant was concentrated under reduced pressure to obtain thetitle compound (106 g (yield: 95%)) as a white solid.

23e Methyltrans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexanecarboxylate

The compound of Example 19(19c): methyltrans-4-[(methylimino)(methylsulfanyl)methyl]cyclohexanecarboxylate (20g, 87 mmol) was dissolved in ethanol (200 mL). To this, the compound ofExample 23(23d): 2-{[4-(trifluoromethyl)pyridin-2-yl]oxy}acetohydrazide(20.5 g, 87 mmol) was added, and the mixture was stirred at 90° C. for 4hours.

The residue obtained by concentration under reduced pressure waspurified by silica gel column chromatography [elution solvent:methanol/dichloromethane=0/1-1/9 (V/V)] to obtain the title compound(19.7 g (yield: 57%)) as a white solid.

23f{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}methanol

The compound of Example 23(23e): methyltrans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexanecarboxylate(19.7 g, 49.4 mmol) was dissolved in tetrahydrofuran (250 mL). To this,a lithium aluminium hydride-tetrahydrofuran solution (2.5 M, 20 mL) wasadded under ice-cooling, and the mixture was stirred at room temperaturefor 25 minutes.

To the reaction mixture, water (1.9 mL), a 15% aqueous sodium hydroxidesolution (1.9 mL), and water (5.7 mL) were sequentially added underice-cooling, and the mixture was diluted with ethyl acetate and thenfiltered with celite. The filtrate was concentrated under reducedpressure to obtain the title compound (17.9 g (yield: 98%)) as a lightyellow oily substance.

23gtrans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexanecarbaldehyde

The compound of Example 23(23f):{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}methanol(17.9 g, 48.3 mmol) was dissolved in dichloromethane (300 mL). To this,Dess-Martin Periodinane (22.4 g, 52.8 mmol) was added under ice-cooling,and the mixture was stirred for 5 minutes under ice-cooling and at roomtemperature for 40 minutes.

The reaction solution was ice-cooled. To this, a 1N aqueous sodiumhydroxide solution (230 mL) and a 10% aqueous sodium thiosulfatesolution were added and stirred, and then the mixture was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate. The residue obtained by concentration under reduced pressurewas purified by silica gel column chromatography [elution solvent:methanol/ethyl acetate=0/1-1/9 (V/V)] to obtain the title compound (11.6g (yield: 65%)) as a white solid.

23h{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}acetaldehyde

(Methoxymethyl)triphenylphosphonium chloride (13.2 g, 38.4 mmol) wassuspended in tetrahydrofuran (100 mL). To this, potassium tert-butoxide(4.31 g, 38.4 mmol) was added under ice-cooling and the mixture wasstirred for 20 minutes. The resultant solution was added dropwise usinga cannula to a solution of the compound of Example 23(23 g):trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexanecarbaldehyde(9.44 g, 25.6 mmol) in tetrahydrofuran (150 mL). After 45 minutes, to asuspension of (methoxymethyl) triphenylphosphonium chloride (8.79 g,25.6 mmol) in tetrahydrofuran (100 mL), potassium tert-butoxide (2.88 g,25.6 mmol) was added under ice-cooling, and the mixture was stirred for5 minutes. The obtained solution was added dropwise again to thereaction solution using a cannula.

After 10 minutes, water was added to the reaction solution, and themixture was concentrated under reduced pressure and extracted with ethylacetate. The organic layer was washed with saturated saline, and thendried over anhydrous sodium sulfate. After filtration, the residueobtained by concentration under reduced pressure was purified by silicagel column chromatography [elution solvent: ethyl acetate/hexane=1/1,ethyl acetate alone, methanol/ethyl acetate=1/9 (V/V)]. The obtained2-[(5-{trans-4-[2-methoxyethenyl]cyclohexyl}-4-methyl-4H-1,2,4-triazol-3-yl)methoxy]-4-(trifluoromethyl)pyridine(10.7 g) was dissolved by adding tetrahydrofuran (100 mL), and 1Nhydrochloric acid (70 mL) was added, then the mixture was stirred atroom temperature for 2.5 hours.

The reaction solution was ice-cooled and 2N aqueous sodium hydroxide (35mL) was added thereto and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated saline, and then dried overanhydrous sodium sulfate. After filtration, the residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: methanol/ethyl acetate=0/1-1/9 (V/V)]to obtain the title compound (6.87 g (yield: 70%)) as a colorless oilysubstance.

23i2-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}prop-2-enal

The compound of Example 23(23h):(trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl} acetaldehyde (6.87 g, 18 mmol) was dissolved inN,N-dimethylformamide (40 mL). To this, a formaldehyde solution (37%)(6.6 mL, 89.8 mmol) and L-proline (618 mg, 5.39 mmol) were added, andthe mixture was stirred at room temperature for 14 hours.

The reaction mixture was diluted with ethyl acetate and washed withwater and saturated saline. The organic layer was dried over anhydroussodium sulfate. After filtration, the residue obtained by concentrationunder reduced pressure was purified by silica gel column chromatography[elution solvent: ethyl acetate/hexane=1/2, ethyl acetate alone,methanol/ethyl acetate=1/9 (V/V)] to obtain the title compound (3.68 g(yield: 52%)) as a white solid.

23j2-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}oxirane-2-carbaldehyde

The compound of Example 23(23i):2-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl} prop-2-enal (3.68 g, 9.33 mmol) was dissolved in methanol(60 mL). To this, a hydrogen peroxide solution (30%) (1.33 mL, 14 mmol)and a 5N aqueous sodium hydroxide solution (0.47 mL, 2.33 mmol) weresequentially added under ice-cooling and the mixture was stirred for 1hour.

To the reaction mixture, a 10% aqueous sodium thiosulfate solution wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated saline, and then dried overanhydrous sodium sulfate. The mixture was concentrated under reducedpressure, then dichloromethane was added. The mixture was azeotropicallyconcentrated to obtain the title compound (3.4 g (yield: 89%)) as awhite solid.

23k4-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]morpholine

The compound of Example 23(23j):2-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}oxirane-2-carbaldehyde(237 mg, 0.58 mmol) was dissolved in ethanol (29 mL). To this, asolution of the compound of Example 23(23b):4-(trans-4-hydrazinylcyclohexyl) morpholine hydrochloride (150 mg, 0.64mmol) in ethanol (5 mL) was added dropwise, and the mixture was stirredat room temperature for 2.5 hours, then stirred at 50° C. for 15.5hours.

The residue obtained by concentration under reduced pressure waspurified by silica gel column chromatography [elution solvent:hexane/ethyl acetate=1/4-0/1 (V/V)] to obtain the title compound (151 mg(yield: 46%)) as a white solid.

Example 246-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-2-oxa-6-azaspiro[3.3]heptane24a Benzyl 3-(trichloromethyl)oxaziridine-2-carboxylate

Benzyl (triphenyl-λ⁵-phosphanilidene)carbamate (CAS Registry Number:81357-08-6, WO2012031298) (240 g, 583 mmol) was dissolved in toluene(600 mL). To this, 2,2,2-trichloroacetaldehyde (111 g, 758 mmol) wasadded, and the mixture was stirred at 110° C. for 1 hour.

The residue obtained by concentration under reduced pressure wasdissolved in hexane (100 mL). The reaction solution was stirred for 30minutes and insoluble matters were removed by filtration, then thefiltrate was concentrated under reduced pressure to obtainbenzyl(2,2,2-trichloroethylidene)carbamate (150 g) as a crude product.

The resultant crude product: benzyl (2,2,2-trichloroethylidene)carbamate(150 g) was dissolved in chloroform (3 L). To this, a solution ofpotassium carbonate (300 g, 2.17 mol) in water (3 L) and a solution ofoxon (300 g, 488 mmol) in water (3 L) were added, and the mixture wasstirred at 0° C. for 1 hour. The aqueous layer was separated, andfreshly prepared solutions of potassium carbonate (300 g, 2.17 mol) inwater (3 L) and of oxon (300 g, 488 mmol) in water (3 L) were added, andthe mixture was stirred at 0° C. for 1 hour. This procedure was repeated5 times, and then the reaction solution was extracted with chloroform.The combined organic layer was washed with saturated saline and driedover anhydrous sodium sulfate. The residue obtained by concentrationunder reduced pressure was purified by silica gel column chromatography[elution solvent: dichloromethane alone] to obtain the title compound(84 g (yield: 57%)) as a yellow oily substance.

24b Benzyl [trans-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl]carbamate

Oxetane-3,3-diyldimethanol (Heat-Biochem, Catalog Number: HB-0630) (11.4g, 96.6 mmol) was suspended in dichloromethane (200 mL). To this,N,N-diisopropylethylamine (140 mL, 805 mmol) was added and thentrifluoromethanesulfonic acid anhydride (32.5 mL, 193 mmol) was addeddropwise at −78° C. The mixture was stirred at −78° C. for 10 minutes,then the temperature was raised to ice-cooling and the mixture wasstirred for 5 minutes. To the reaction mixture, a solution ofbenzyl(trans-4-aminocyclohexyl)carbamate (CAS Registry Number:149423-77-8, WO1992021361) (20 g, 80.5 mmol) in acetonitrile (100 mL)was added, and the mixture was stirred for 15 minutes under ice-cooling,then the mixture was stirred at room temperature for 3 hours.

The reaction solution was diluted with dichloromethane and thenextracted with dichloromethane. The organic layer was washed with waterand saturated saline and dried over anhydrous sodium sulfate. To theresidue obtained by concentration under reduced pressure, ethyl acetateand hexane were added, and the obtained solid was collected byfiltration to obtain the title compound (14 g) as a white solid.Furthermore, the mother liquid was concentrated under reduced pressureand the obtained residue was purified by NH silica gel columnchromatography [elution solvent: hexane/ethyl acetate=1/1-0/1 (V/V)] toobtain the title compound (2.5 g). Combined with the above-describedobtained title compound, the title compound (16.5 g (yield: 62%)) wasobtained as a white solid.

24c trans-4-(2-Oxa-6-azaspiro[3.3]hept-6-yl)cyclohexanamine

The compound of Example 24(24b): benzyl [trans-4-(2-oxa-6-azaspiro [3.3]hept-6-yl)cyclohexyl]carbamate (14 g, 42.4 mmol) was dissolved inethanol (200 mL). To this, 10% palladium carbon catalyst (1.4 g) wasadded and the mixture was stirred at room temperature for 2 hours undera hydrogen atmosphere.

To the reaction mixture, ethanol was added, then palladium-carbon wasfiltered off, and the filtrate was washed with ethanol. The resultantwas concentrated under reduced pressure to obtain the title compound(8.2 g (yield: 100%)) as a white solid.

24d Benzyl2-[trans-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl]hydrazinecarboxylate

The compound of Example 24(24c):trans-4-(2-oxa-6-azaspiro[3.3]hepta-6-yl)cyclohexanamine (8.2 g, 42mmol) was dissolved in dichloromethane (80 mL). To this, a solution ofthe compound of Example 24(24a): benzyl3-(trichloromethyl)oxaziridine-2-carboxylate (11 g, 29 mmol) indichloromethane (80 mL) was added dropwise at −65° C. The mixture wasstirred at −65° C. for 10 minutes, then the temperature was raised toice-cooling.

To the reaction mixture, diisopropylamine (12 mL, 84 mmol) was added,and the mixture was stirred for 15 minutes. Then, a saturated aqueousammonium chloride solution was added to separate liquids, and theorganic layer was washed with saturated saline. The organic layer wasdried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by NH silica gelcolumn chromatography [elution solvent: hexane/ethyl acetate=1/1-0/1(V/V)] to obtain the title compound (5.8 g (yield: 40%)) as a whitesolid.

24e 6-(trans-4-Hydrazinylcyclohexyl)-2-oxa-6-azaspiro[3.3]heptaneacetate

The compound of Example 24(24d): benzyl[trans-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl]hydrazinecarboxylate (5.8 g, 17 mmol) was dissolved in ethanol (60 mL). To this,acetic acid (1.2 mL, 20 mmol) and 102 palladium carbon catalyst (0.6 g)were added and the mixture was stirred at room temperature for 1 hourunder a hydrogen atmosphere. To the reaction mixture, acetic acid (1.2mL, 20 mmol) was added, and the reaction mixture was stirred under ahydrogen atmosphere at room temperature for 1 hour. To the reactionmixture, acetic acid (2.3 mL, 40 mmol) was added, and the reactionmixture was stirred under a hydrogen atmosphere at room temperature for2 hours.

To the reaction mixture, ethanol was added, then palladium-carbon wasfiltered off, and the filtrate was washed with ethanol. To this, toluenewas added, and the mixture was azeotropically concentrated, andconcentrated under reduced pressure to obtain the title compound (4.5 g(yield: 99%)) as a light yellow oily substance.

24f6-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-2-oxa-6-azaspiro[3.3]heptane

The compound of Example 23(23j):2-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}oxirane-2-carbaldehyde(6 g, 14.6 mmol) was dissolved in ethanol (25 mL). To this, the compoundof Example 24(24e):6-(trans-4-hydrazinylcyclohexyl)-2-oxa-6-azaspiro[3.3]heptane acetate(4.76 g, 17.5 mmol) was added, and the mixture was stirred at roomtemperature, and allowed to stand still overnight.

To this, toluene was added, and the reaction solvent was distilled awayunder reduced pressure and the resultant residue was purified by NHsilica gel column chromatography [elution solvent: methanol/ethylacetate=0/1-1/19 (V/V)] to obtain the title compound (4.1 g (yield:48%)) as a white solid.

Example 256-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-1-oxa-6-azaspiro[3.3]heptane25a Benzyl[trans-4-(4-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]carbamate

Benzyl (trans-4-hydrozinylcyclohexyl)carbamate hydrochloride (CASRegistry Number: 1607494-41-6, WO2014064219) (442 mg, 1.47 mmol) wassuspended in ethanol (10 mL). To this, the compound of Example 23(23j):2-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}oxirane-2-carbaldehyde (504 mg, 1.23 mmol) was added and themixture stirred at room temperature for 43 hours.

The solvent was distilled away under reduced pressure and the resultantresidue was purified by NH silica gel column chromatography [elutionsolvent: hexane/dichloromethane/ethyl acetate=2/8/0-0/2/8 (V/V/V)]. Theresultant crude product was washed with ethyl acetate to obtain thetitle compound (663 mg (yield: 85%)) as a white solid.

25btrans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexanamine

The compound of Example 25(25a): benzyl[trans-4-(4-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]carbamate(300 mg, 0.47 mmol) was dissolved in methanol (6 mL) and dichloromethane(1 mL). To this, acetic acid (0.14 mL, 2.4 mmol) and 10% palladiumcarbon catalyst (150 mg) were added at room temperature and the mixturewas stirred at room temperature for 4 hours under a hydrogen atmosphere.

Palladium-carbon was filtered off, and the mixture was washed withdichloromethane. The resultant was concentrated under reduced pressureand the solvent was azeotropically concentrated with ethanol andtoluene, and the resultant residue was purified by silica gel columnchromatography [elution solvent: methanol/dichloromethane=0/1-1/19(V/V)] to obtain the title compound (217 mg (yield: 92%)) as a whitesolid.

25c Oxetane-2,2-diyldimethanol

Diethyl oxetane-2,2-dicarboxylate (CAS Registry Number: (1384465-73-9,Synthesis (2012), 44 (10), 1584-1590) (4 g, 19.8 mmol) and lithiumchloride (2.52 g, 59.4 mmol) were dissolved in tetrahydrofuran (20 mL)and methanol (40 mL). To this, sodium borohydride (2.25 g, 59.4 mmol)was added under ice-cooling, and then the mixture was stirred at 0° C.for 30 minutes, then at 20° C. for 18.5 hours.

To the reaction mixture, an aqueous potassium sodium tartrate solutionwas added, and the mixture was stirred at 20° C. for 30 minutes, andthen extracted with ethyl acetate and dichloromethane. The combinedorganic layer was dried over anhydrous sodium sulfate. The residueobtained by concentration under reduced pressure was purified by silicagel column chromatography [elution solvent: ethyl acetate/petroleumether=1/2-1/1 (V/V), 5% methanol] to obtain the title compound. Theaqueous layer was re-extracted with chloroform/isopropanol (4/1 (V/V)),and the combined organic layer was dried over anhydrous sodium sulfate.The residue obtained by concentration under reduced pressure waspurified by silica gel column chromatography [elution solvent: ethylacetate/petroleum ether=1/2-1/1 (V/V), 5% methanol] to obtain the titlecompound (1.75 g (yield: 75%)) as a colorless oily substance.

25d6-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-1-oxa-6-azaspiro[3.3]heptane

The compound of Example 25(25c): oxetane-2,2-diyldimethanol (75 mg, 0.63mmol) and N,N-diisopropylethylamine (0.72 mL, 4.23 mmol) were dissolvedin dichloromethane (1.5 mL). The mixture was cooled to −78° C., thentrifluoromethanesulfonic acid anhydride (0.21 mL, 1.27 mmol) was addeddropwise thereto. The mixture was stirred at −78° C. for 15 minutes. Tothis, a solution of the compound of Example 25(25b):trans-4-(4-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexanamine(213 mg, 0.42 mmol) in dichloromethane (5 mL) was added at 0° C., andthe mixture was stirred at 0° C. for 15 minutes and then stirred at roomtemperature for 18 hours.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent:methanol/dichloromethane=0/1-1/99 (V/V)]. To the obtained crude product,diethyl ether was added, and the precipitated solid was collected byfiltration to obtain of the title compound (76 mg (yield: 31%)) as awhite solid.

Example 266-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-2-oxa-6-azaspiro[3.4]octane26a Benzyl 2-(4-oxocyclohexyl)hydrazinecarboxylate

Benzyl 2-(1,4-dioxaspiro[4.5]dec-8-yl)hydrazine carboxylate (CASRegistry Number: 1630725-36-8, WO2014163146) (1.5 g, 4.9 mmol) wasdissolved in tetrahydrofuran (9.8 mL). To this, 1N hydrochloric acid(9.8 mL, 9.8 mmol) was added and the mixture was stirred at roomtemperature for 1 hour and then stirred at 50° C. for 5 hours.

To the residue obtained by concentration under reduced pressure, ethylacetate was added, and the mixture was neutralized by adding 1N sodiumhydroxide (10 mL, 10 mmol). To the reaction mixture, water (20 ml) wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated saline, and dried over anhydroussodium sulfate. The resultant was concentrated under reduced pressure toobtain the title compound (1.27 g (yield: 99%)) as a white solid.

26b Benzyl2-[trans-4-(2-oxa-6-azaspiro[3.4]oct-6-yl)cyclohexyl]hydrazinecarboxylate

2-Oxa-6-azaspiro[3.4]octane (J&W-PharmLab, Catalog Number: 75R0364) (500mg, 4.42 mmol) was dissolved in methanol/dichloromethane (1/1 (V/V))(8.8 mL). To this, the compound of Example 26(26a): benzyl2-(4-oxocyclohexyl)hydrazinecarboxylate (5.06 g, 30.5 mmol) was added atroom temperature, and the mixture was stirred at room temperature for 15minutes. To the reaction mixture, acetic acid (0.76 ml, 13.3 mmol) andsodium cyanoborohydride (2.34 g, 8.84 mmol) were added, and the mixturewas stirred at room temperature for 16 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with dichloromethane. The organiclayer was washed with saturated saline, and then dried over anhydroussodium sulfate. The residue obtained by concentration under reducedpressure was purified by NH silica gel column chromatography [elutionsolvent: hexane/ethyl acetate=7/3-1/4 (V/V)]. To the obtained crudeproduct, diisopropyl ether was added and trituration was performed toobtain the title compound (154 mg (yield: 10%)) as a white solid.

26c6-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-2-oxa-6-azaspiro[3.4]octane

The compound of Example 26(26b)): benzyl2-[trans-4-(2-oxa-6-azaspiro[3.4]octa-6-yl)cyclohexyl}]hydrazinecarboxylate (150 mg, 0.42 mmol) was dissolved in ethanol (3 mL). Tothis, acetic acid (0.119 mL, 2.09 mmol) and 10% palladium on carboncatalyst (45 mg) were added, and the mixture was stirred at roomtemperature for 5 hours under a hydrogen atmosphere.

Palladium-carbon was filtered off, and the filtrate was washed withethanol. The residue obtained by concentration under reduced pressurewas dissolved in ethanol (15 mL). To this, the compound of Example23(23j):2-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}oxirane-2-carbaldehyde(119 mg, 0.42 mmol) in ethanol (6 mL) was added and the mixture wasstirred at room temperature for 18.5 hours.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent: ethylacetate alone] to obtain the title compound (50 mg (yield: 20%)) as awhite solid.

Example 272-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-6-oxa-2-azaspiro[3.4]octane27a 2-(1,4-Dioxaspiro[4.5]dec-8-yl)-6-oxa-2-azaspiro[3.4]octane

2-Benzyl-6-oxa-2-azaspiro[3.4]octane (CAS Registry Number: 1419590-34-3,WO2013011285) (2 g, 9.84 mmol) was dissolved in ethanol (40 mL). Tothis, acetic acid (2.81 mL, 49.2 mmol) and 10% palladium carbon catalyst(1 g) were added, and the mixture was stirred under a hydrogenatmosphere at room temperature for 23 hours.

Palladium-carbon was filtered off, and the filtrate was washed withethanol. After concentration under reduced pressure, a crude product6-oxa-2-azaspiro[3.4]octaneacetate (3.15 g) was obtained as a lightbrown oily substance.

The obtained crude product 6-oxa-2-azaspiro[3.4]octaneacetate (3.15 g)was dissolved in ethanol (40 mL). To this, 1,4-dioxaspiro [4.5]decan-8-one (Tokyo Chemical Industry Co., Ltd., Catalog Number: C1292)(1.54 g, 9.84 mmol) was added, and the mixture was stirred at roomtemperature for 20 minutes. To the reaction mixture, sodiumcyanoborohydride (1.24 g, 19.7 mmol) was added, and the mixture wasstirred at room temperature for 22 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with dichloromethane. The organiclayer was washed with saturated saline, and then dried over anhydroussodium sulfate. The residue obtained by concentration under reducedpressure was purified by NH silica gel column chromatography [elutionsolvent: hexane/ethyl acetate=1/0-1/1 (V/V)] to obtain the titlecompound (2.36 g (yield: 95%)) as a white solid.

27b 4-(6-Oxa-2-azaspiro[3.4]oct-2-yl)cyclohexanone

The compound of Example 27(27a):2-(1,4-dioxaspiro[4.5]deca-8-yl)-6-oxa-2-azaspiro[3.4]octane (1.01 g,3.98 mmol) was dissolved in tetrahydrofuran (8 mL). To this, 1Nhydrochloric acid (8 mL, 8 mmol) was added, and the mixture was stirredat 50° C. for 66 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with dichloromethane. The organiclayer was washed with saturated saline, and then dried over anhydroussodium sulfate. The resultant was concentrated under reduced pressure toobtain the title compound (0.85 g (quantitative)) as a light brown oilysubstance.

27c Benzyl2-[trans-4-(6-oxa-2-azaspiro[3.4]oct-2-yl)cyclohexyl]hydrazinecarboxylate

The compound of Example 27(27b):4-(6-oxa-2-azaspiro[3.4]oct-2-yl)cyclohexanone (833 mg, 3.98 mmol) wasdissolved in methanol (16 mL). To this, benzyl carbazate (Tokyo ChemicalIndustry Co., Ltd., Catalog Number: C1564) (661 mg, 3.98 mmol) was addedat room temperature, and the mixture was stirred at room temperature for20 minutes. To the reaction mixture, acetic acid (0.46 ml, 7.96 mmol)and sodium cyanoborohydride (500 g, 7.96 mmol) were added, and themixture was stirred at room temperature for 17 hours.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with dichloromethane. The organiclayer was washed with saturated saline, and then dried over anhydroussodium sulfate. The residue obtained by concentration under reducedpressure was purified by NH silica gel column chromatography [elutionsolvent: hexane/ethyl acetate=65/35-0/1 (V/V)]. To the obtained crudeproduct, diisopropyl ether was added, and trituration was performed toobtain the title compound (822 mg (yield: 58%)) as a white solid.

27d2-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-6-oxa-2-azaspiro[3.4]octane

The compound of Example 27(27c): benzyl2-[trans-4-(6-oxa-2-azaspiro[3.4]octa-2-yl)cyclohexyl]hydrazinecarboxylate (200 mg, 0.56 mmol) was dissolved in ethanol (4 mL). Tothis, acetic acid (0.159 mL, 2.78 mmol) and 10% palladium on carboncatalyst (100 mg) was added, and the mixture was stirred at roomtemperature for 4 hours under a hydrogen atmosphere.

Palladium-carbon was filtered off, and the filtrate was washed withethanol. The residue obtained by concentration under reduced pressurewas dissolved in ethanol (7 mL). To this, a solution of the compound ofExample 23(23j):2-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}oxirane-2-carbaldehyde(208 mg, 0.51 mmol) in ethanol (18 mL) was added, and the mixture wasstirred at 50° C. for 16 hours.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent:hexane/ethyl acetate=2/8-0/1 (V/V)] to obtain the title compound (92 mg(yield: 30%)) as a white solid.

Example 28(1SR,2SR,4RS)-2-(Azetidin-1-yl)-4-(4-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclopentanol28a2-[(1RS,3SR,4SR)-3-Azido-4-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]-1H-isoindole-1,3(2H)-dione

2-[(1RS,3SR,4SR)-3-Azido-4-hydroxycyclopentyl]-1H-isoindol-1,3(2H)-dione(600 mg, 2.2 mmol) synthesized according to a reference document (Arch.Pharm. Chem. Life Sci. 2012, 345, 677-686) was dissolved inN,N-dimethylformamide (10 mL). To this, imidazole (0.39 g, 5.8 mmol) andtert-butyldiphenylchlorosilane (790 mg, 2.9 mmol) were added and themixture was stirred at room temperature for 6 hours.

The reaction mixture was diluted with ethyl acetate and washed withwater. The organic layer was washed with saturated saline, and driedover anhydrous sodium sulfate. The residue obtained by concentrationunder reduced pressure was purified by silica gel column chromatography[elution solvent: hexane/ethyl acetate=97/3-7/3 (V/V)] to obtain thetitle compound (0.95 g (yield: 84%)) as a light yellow solid.

28b2-[(1RS,3SR,4SR)-3-Amino-4-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]-1H-isoindole-1,3(2H)-dione

The compound of Example 28(28a):2-[(1RS,3SR,4SR)-3-azido-4-{[[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]-1H-isoindole-1,3(2H)-dione(0.1 g, 0.2 mmol) was dissolved in ethanol (5 mL). To this, 10%palladium on carbon catalyst (0.1 g) was added, and the mixture wasstirred at room temperature for 2 hours under a hydrogen atmosphere.

Palladium-carbon was filtered off, and the filtrate was washed withethanol and concentrated under reduced pressure to obtain the titlecompound (95 mg (quantitative)) as a light yellow oily substance.

28c Benzyl[(1SR,2SR,4RS)-2-{[tert-butyl(diphenyl)silyl]oxy}-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclopentyl]carbamate

The compound of Example 28(28b):2-[(1RS,3SR,4SR)-3-amino-4-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]-1H-isoindole-1,3(2H)-dione(95 mg, 0.2 mmol) was dissolved in tetrahydrofuran (2 mL). To this,triethylamine (0.081 mL, 0.59 mmol) and benzyl chloroformate (0.034 mL,0.24 mmol) were added, and the mixture was stirred at room temperaturefor 14 hours.

The reaction mixture was diluted with ethyl acetate and washed withwater. The organic layer was washed with saturated saline, and driedover anhydrous sodium sulfate. The residue obtained by concentrationunder reduced pressure was purified by silica gel column chromatography[elution solvent: hexane/ethyl acetate=9/1-1/1 (V/V)] to obtain thetitle compound (70 mg (yield: 58%)) as a light yellow solid.

28d Benzyl[(1SR,2SR,4RS)-4-amino-2-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]carbamate

The compound of Example 28(28c): benzyl[(1SR,2SR,4RS)-2-{[tert-butyl(diphenyl)silyl]oxy}-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclopentyl]carbamate(70 mg, 0.11 mmol) was dissolved in ethanol (2 mL). To this, hydrazinemonohydrate (0.017 mL, 0.34 mmol) was added, and the mixture was stirredat 90° C. for 3 hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was purified by silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/1-1/9 (V/V)] to obtain the titlecompound (52 mg (yield: 94%)) as a light yellow oily substance.

28e(1SR,2SR,4RS)-2-(Azetidin-1-yl)-4-(4-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclopentanol

The compound of Example 28(28d): benzyl[(1SR,2SR,4RS)-4-amino-2-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]carbamate(837 mg, 1.71 mmol) was dissolved in tetrahydrofuran (20 mL) anddimethylacetamide (10 mL). To this, a solution of tert-butyl3-(trichloromethyl)oxaziridine-2-carboxylate (CAS Registry Number:219547-77-0, WO2012074067) (315 mg, 1.2 mmol) in tetrahydrofuran (3 mL)was added dropwise at −70° C. for 30 minutes. The mixture was stirredfor 1.5 hours while warming to −20° C.

To this, dilute hydrochloric acid and ethyl acetate were added at −20°C., and the mixture was extracted with ethyl acetate. The organic layerwas washed with water and saturated saline and dried over anhydroussodium sulfate. The residue obtained by concentration under reducedpressure was purified by NH silica gel column chromatography [elutionsolvent: hexane/ethyl acetate=8/2-6/4 (V/V)] to obtain the crude productof tert-butyl2-[(1RS,3SR,4SR)-3-{[(benzyloxy)carbonyl]amino}-4-[[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]hydrazinecarboxylate (650 mg) as a colorless oily substance.

Similarly, the compound of Example 28(28d): benzyl[(1SR,2SR,4RS)-4-amino-2-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]carbamate(330 mg, 0.675 mmol) was dissolved in tetrahydrofuran (8 mL) anddimethylacetamide (4 mL). To this, a solution of tert-butyl3-(trichloromethyl)oxadiridine-2-carboxylate (CAS Registry Number:219547-77-0, WO2012074067) (124 mg, 0.472 mmol) in tetrahydrofuran (1mL) was added dropwise at −60° C. for 30 minutes. The mixture wasstirred for 1 hour while warming to −20° C.

To the reaction mixture, dilute hydrochloric acid and ethyl acetate wasadded at −20° C., and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated saline and dried overanhydrous sodium sulfate. The residue obtained by concentration underreduced pressure was combined with the above-described crude product,and the mixture was purified by NH silica gel column chromatography[elution solvent hexane/ethyl acetate=9/1-7/3 (V/V)] to obtaintert-butyl2-[(1RS,3SR,4SR)-3-{[(benzyloxy)carbonyl]amino}-4-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]hydrazinecarboxylate(518 mg) as a colorless oily substance.

The obtained tert-butyl2-[(1RS,3SR,4SR)-3-{[(benzyloxy)carbonyl]amino}-4-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]hydrazinecarboxylate (518 mg, 0.86 mmol) wasdissolved in ethanol (15 mL). To this, a 10% palladium carbon catalyst(100 mg) was added, and the mixture was stirred under a hydrogenatmosphere at room temperature for 2 hours and then stirred at 60° C.for 2 hours.

Palladium-carbon was filtered off, and the filtrate was washed withethyl acetate. The residue obtained by concentration under reducedpressure was dissolved in tetrahydrofuran (15 mL). To this, a 10%palladium carbon catalyst (100 mg) was added, and the mixture wasstirred under a hydrogen atmosphere at room temperature for 18 hours andthen stirred at 60° C. for 32 hours.

Palladium-carbon was filtered off, and the filtrate was washed withethyl acetate. The residue obtained by concentration under reducedpressure was purified by NH silica gel column chromatography [elutionsolvent: hexane/ethyl acetate=9/1-2/8 (V/V)] to obtain tert-butyl2-[(1RS,3SR,4SR)-3-amino-4-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]hydrazinecarboxylate(215 mg) as a colorless oily substance.

The obtained tert-butyl 2-[(1RS,3SR,4SR)-3-amino-4-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]hydrazine carboxylate (212 mg, 0.451mmol) was dissolved in acetonitrile (10 mL). To this, potassiumcarbonate (310 mg, 2.24 mmol) and 1,3-dibromopropane (Tokyo ChemicalIndustry Co., Ltd., Catalog Number: D0202) (145 mg, 0.718 mmol) wereadded and the mixture was stirred at 90° C. for 4.5 hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was subjected to NH silica gel column chromatography [elutionsolvent: hexane/ethyl acetate=9/1-4/6 (V/V)] to obtain tert-butyl2-[(1RS,3SR,4SR)-3-(azetidin-1-yl)-4-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]hydrazinecarboxylate (163 mg) as acolorless oily substance.

The obtained tert-butyl2-[(1RS,3SR,4SR)-3-(azetidin-1-yl)-4-([tert-butyl(diphenyl)silyl]oxy}cyclopentyl]hydrazinecarboxylate (160 mg, 0.314mmol) was dissolved in methanol (2 mL). To this, 4N hydrochloricacid-1,4-dioxane (4 mL, 16 mmol) was added, and the mixture was stirredat room temperature for 2 hours.

To the residue obtained by concentrating the reaction mixture underreduced pressure, ethanol was added, and the mixture was azeotropicallyconcentrated to obtain1-[(1SR,2SR,4RS)-2-{[tert-butyl(diphenyl)silyl]oxy}-4-hydrazinylcyclopentyl]azetidinehydrochloride (176 mg) as a colorless oily substance.

The obtained1-[(1SR,2SR,4RS)-2-{[tert-butyl(diphenyl)silyl]oxy}-4-hydrozinylcyclopentyl]azetidinehydrochloride (176 mg, 0.429 mmol) and the compound of Example 23(23j):2-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}oxirane-2-carbaldehyde(117 mg, 0.285 mmol) were dissolved in ethanol (15 mL) and the mixturewas stirred at room temperature for 18 hours.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solventhexane/ethyl acetate=9/1-0/1 (V/V)] to obtain2-{[5-(trans-4-{1-[(1RS,3SR,4SR)-3-(azetidin-1-yl)-4-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]-1H-pyrazol-4-yl}cyclohexyl)-4-methyl-4H-1,2,4-triazol-3-yl]methoxy}-4-(trifluoromethyl)pyridine(52 mg) as an colorless oily substance.

The obtained2-{[5-(trans-4-{1-[(1RS,3SR,4SR)-3-(azetidin-1-yl)-4-{[tert-butyl(diphenyl)silyl]oxy}cyclopentyl]-1H-pyrazol-4-yl}cyclohexyl)-4-methyl-4H-1,2,4-triazol-3-yl]methoxy}-4-(trifluoromethyl)pyridine (52 mg, 0.066 mmol) was dissolvedin tetrahydrofuran (2 mL). To this, a 1M tetrabutylammoniumfluoride-tetrahydrofuran solution (0.2 mL, 0.2 mmol) was added and themixture was stirred at 70° C. for 3 hours.

The reaction mixture was diluted with ethyl acetate and washed withwater. The organic layer was washed with saturated saline, and driedover anhydrous sodium sulfate. The residue obtained by concentrationunder reduced pressure was azeotropically concentrated withacetonitrile, then ethyl acetate was added. The mixture was filtered andthen washed with ethyl acetate. The obtained crude product was purifiedby NH silica gel column chromatography [elution solvent: hexane/ethylacetate=7/3-0/1 (V/V)] to obtain the title compound (20.1 mg (yield:2.4%)) as a white solid.

Example 29{1-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]azetidine-3,3-diyl}dimethanol

The compound of Example 24(24f):6-[trans-4-(4-{trans-4-[4-methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-2-oxa-6-azaspiro[3.3]heptane(100 mg, 0.17 mmol) was dissolved in 1,4-dioxane (4 mL). To this,sulfuric acid (0.57 mL, 10.6 mmol) was added and the mixture was stirredat 70° C. for 2 hours. To the reaction mixture, water (4 mL) was added,and the mixture was stirred at 70° C. for 3 hours.

To the reaction mixture, dichloromethane and saturated aqueous sodiumbicarbonate were added under ice-cooling, and the mixture was extractedwith dichloromethane. The organic layer was washed with saturatedsaline, and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by thin layer silicagel chromatography [developing solvent: dichloromethane/methanol=3/1(V/V)] to obtain the title compound (13 mg (yield: 12%=)) as a whitesolid.

Example 30 Methyl3-{[5-(trans-4-{1-[trans-4-(azetidin-1-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4-methyl-4H-1,2,4-triazol-3-yl]methoxy}benzoate30a 4-(Azetidin-1-yl)cyclohexanone

4-aminocyclohexanone hydrochloride (CAS Registry Number: 675112-40-0,WO2004024728) (40 g, 267 mmol) was dissolved in acetonitrile. To this,potassium carbonate (180 g, 1.3 mol) and 1,3-dibromopropane (27 mL, 265mmol) were added, and the mixture was stirred at 70° C. for 10 hours.

The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography [elution solvent:methanol/dichloromethane=0/1-1/40 (V/V), 0.1% ammonia water] to obtainthe title compound (13 g (yield: 29%)) as a yellow oily substance.

30b tert-Butyl 2-[trans-4-(azetidin-1-yl)cyclohexyl]hydrazinecarboxylate

The compound of Example 30(30a): 4-azetidin-1-yl)cyclohexanone (12 g,78.3 mmol) was dissolved in methanol (100 mL). To this, sodium carbonate(45 g, 317 mmol) and tert-butyl carbazate (10.5 g, 79.1 mmol) wereadded, and the mixture was stirred at 15° C. for 1 hour.

The residue obtained by concentrating the reaction mixture under reducedpressure was dissolved in a mixed solvent of dichloromethane (24 mL) andmethanol (6 mL). To this, sodium borohydride (7.22 g, 190.74 mmol) wasadded and the mixture was stirred at 15° C. for 12 hours.

To the reaction mixture, water was added, and the mixture was extractedwith ethyl acetate. The combined organic layer was washed with saturatedsaline and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was dissolved in a mixed solvent ofmethanol/ethyl acetate (1/20 (V/V), 42 mL). To this, petroleum ether wasadded, and the precipitated solid was collected by filtration to obtaina crude product. The obtained crude product was purified by highperformance liquid chromatography to obtain the title compound (3.1g(yield: 17%)) as a white solid.

30c 1-(trans-4-Hydrazinylcyclohexyl)azetidine hydrochloride

The compound of Example 30(30b): tert-butyl2-[trans-4-azetidin-1-yl)cyclohexyl]hydrazine carboxylate (2.9 g, 10.2mmol) was dissolved in dichloromethane (35 mL). To this, 4N hydrochloricacid-ethyl acetate (14.5 mL, 58 mmol) was added, and the mixture wasstirred at 15° C. for 10 hours.

The reaction mixture was concentrated under reduced pressure to obtainthe title compound (2.43 g (yield: 98%)) as a white solid.

30d{trans-4-[5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}acetaldehyde

(Methoxymethyl)triphenylphosphonium chloride (27.8 g, 81 mmol) wassuspended by adding tetrahydrofuran (200 mL). To this, potassiumtert-butoxide (9.12 g, 81 mmol) was added under ice-cooling and themixture was stirred for 10 minutes. The obtained solution was addeddropwise while stirring, using a cannula, to a solution of the compoundof Example 20(20c):trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexanecarbaldehyde(18.7 g, 40.5 mmol) in tetrahydrofuran (200 mL) under ice-cooling. Themixture was stirred for 10 minutes under ice-cooling.

To the reaction solution, water was added, and the mixture wasconcentrated to about half volume under reduced pressure, then extractedwith ethyl acetate, and dried over anhydrous sodium sulfate. The residueobtained by concentration under reduced pressure was purified by silicagel column chromatography [elution solvent dichloromethane/ethylacetate=1/0-0/1 (V/V)]. The obtained residue was dissolved in toluene(200 mL). To this, magnesium chloride (11.6 g, 122 mmol) was added andthe mixture was stirred at 60° C. for 1.5 hours. After the mixture wascooled to room temperature, insoluble matters were filtered. The residueobtained by concentration under reduced pressure was dissolved by addingtetrahydrofuran (160 mL). To this, 1N hydrochloric acid (80 mL) wasadded under ice-cooling, and the mixture was stirred for 8 hours.

The mixture was ice-cooled, and neutralized by adding a 1N aqueoussodium hydroxide solution (80 mL) dropwise, and extracted with ethylacetate. The organic layer was washed with saturated saline, and thendried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: ethyl acetate/hexane=1/1, ethyl acetatealone, methanol/ethyl acetate=9/1 (V/V)] to obtain the title compound(9.44 g (yield: 55%)) as a white solid.

30e2-{trans-4-[5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}prop-2-enal

The compound of Example 30(30d):{trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}acetaldehyde(9.44 g, 19.8 mmol) was dissolved in N,N-dimethylformamide (50 mL). Tothis, a formaldehyde solution (37%) (7.3 mL, 99.2 mmol) and L-proline(685 mg, 5.95 mmol) were added and the mixture was stirred at roomtemperature for 16 hours.

The reaction solution was diluted with ethyl acetate, and sequentiallywashed with saline, water and saturated saline, and dried over anhydroussodium sulfate. The residue obtained by concentration under reducedpressure was purified by silica gel column chromatography [elutionsolvent: ethyl acetate/hexane=1/1, ethyl acetate alone, methanol/ethylacetate=1/9 (V/V)] to obtain the title compound (8.52 g (yield: 88%)) asa white solid.

30f2-{trans-4-[5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}oxirane-2-carbaldehyde

The compound of Example 30(30e):2-{trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}prop-2-enal(8.52 g, 17.5 mmol) was dissolved in methanol (80 mL). To this, hydrogenperoxide (30%) (2.5 mL, 26.2 mmol) and sodium hydroxide (380 mg, 8.73mmol) were added under ice-cooling, and the mixture was stirred for 30minutes under ice-cooling.

To the reaction mixture, a 10% aqueous sodium thiosulfate solution wasadded, and the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated saline, and then dried overanhydrous sodium sulfate. To the residue obtained by concentration underreduced pressure, dichloromethane was added, and the mixture wasazeotropically concentrated to obtain the title compound (8.51 g (yield:97%)) as a white solid.

30g3-(trans-4-{1-[trans-4-(Azetidin-1-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazole

The compound of Example 30(30f): 2-{trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}oxirane-2-carbaldehyde(800 mg, 1.59 mmol) was dissolved in ethanol (80 mL). To this, thecompound of Example 30(30c): 1-(trans-4-hydradinylcyclohexyl)azetidinehydrochloride (392 mg, 1.91 mmol) was added, and the mixture was stirredat room temperature for 17 hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was purified by NH silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/1-1/19 (V/V)] to obtain the titlecompound (732 mg (yield: 72%)) as a light brown solid.

30h[5-(trans-4-{1-[trans-4-(Azetidin-1-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4-methyl-4H-1,2,4-triazol-3-yl]methanol

The compound of Example 30(30g):3-(trans-4-{1-[trans-4-(azetidin-1-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazole(728 mg, 1.14 mmol) was dissolved in 1,4-dioxane (15 mL). To this,fluoride, polymer-supported (Sigma-Aldrich, Catalog Number: 387789)(1.83 g, 4.12 mmol) was added, and the mixture was stirred at 100° C.for 25 hours.

The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure. The obtained residue was purified by NH silicagel column chromatography [elution solvent: methanol/ethylacetate=1/9-15/85 (V/V)] to obtain the title compound (334 mg (yield:73%)) as a light brown solid.

30i Methyl3-{[5-(trans-4-{1-[trans-4-(azetidin-1-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4-methyl-4H-1,2,4-triazol-3-yl]methoxy}benzoate

The compound of Example 30(30h):[5-(trans-4-{1-[trans-4-(azetidin-1-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4-methyl-4H-1,2,4-triazol-3-yl]methanol(25 mg, 0.06 mmol) and methyl 3-hydroxybenzoate (Tokyo Chemical IndustryCo., Ltd., Catalog Number: H0215) (104 mg, 0.681 mmol) was suspended in1,4-dioxane (0.5 mL). To this, cyanomethylene tributylphosphorane (0.049mL, 0.19 mmol) was added, and the mixture was stirred at 130° C. for 1hour under microwave irradiation.

Similarly, the compound of Example 30(30h):[5-(trans-4{1-[trans-4-(-azetidin-1-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4-methyl-4H-1,2,4-triazol-3-yl]methanol(150 mg, 0.38 mmol) and methyl 3-hydroxybenzoate (Tokyo ChemicalIndustry Co., Ltd., Catalog Number: H0215) (172 mg, 1.13 mmol) wassuspended in 1,4-dioxane (3 mL). To this, cyanomethylenetributylphosphorane (0.296 mL, 1.13 mmol) was added, and the mixture wasstirred at 130° C. for 1 hour under microwave irradiation.

The resultant was combined with the reaction mixture in which thereaction was performed previously, then the residue obtained byconcentration under reduced pressure was purified by NH silica gelcolumn chromatography [elution solvent: hexane/ethylacetate/methanol=2/8/0-0/97.5/2.5 (V/V/V)] twice. To the obtained crudeproduct, diethyl ether was added, and the precipitated solid wascollected by filtration to obtain the title compound (86 mg (yield:43%)) as a light brown solid.

Example 31 Methyl3-{[4-methyl-5-(trans-4-{1-[trans-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methoxy}benzoate31a6-[trans-4-(4-{trans-4-[5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-2-oxa-6-azaspiro[3.3]heptane

The compound of Example 30(30f):2-trans-4-[5-{[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}oxirane-2-carbaldehyde(730 mg, 1.43 mmol) was dissolved in ethanol (7 mL). The compound ofExample 24(24e):6-(trans-4-hydrazinylcyclohexyl)-2-oxa-6-azaspiro[3.3]heptane acetate(512 mg, 1.43 mmol) was added, and the mixture was stirred at roomtemperature for 16 hours.

The residue obtained by concentrating the reaction mixture under reducedpressure was purified by NH silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=0/1-1/4 (V/V)] to obtain the titlecompound (635 mg (yield: 65%)) as a white solid.

31b[4-Methyl-5-(trans-4-{1-[trans-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methanol

The compound of Example 31(31a):6-[trans-4-(4-{trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-2-oxa-6-azaspiro[3.3]heptane(2.54 g, 3.74 mmol) was dissolved in tetrahydrofuran (30 mL) and water(15 mL). To this, fluoride, polymer-supported (Sigma-Aldrich, CatalogNumber: 387789) (6 g, 15 mmol) was added, and the mixture was stirred at80° C. for 9 hours, and then the reaction solution was cooled to roomtemperature and allowed to stand still for 12 hours. After stirringagain at 80° C. for 12 hours, the reaction solution was cooled to roomtemperature and allowed to stand still for 12 hours. This procedure wasrepeated 3 times.

The reaction mixture was filtered, and the residue obtained byconcentration under reduced pressure was purified by NH silica gelcolumn chromatography [elution solvent: methanol/ethyl acetate=0/1-3/7(V/V)] to obtain the title compound (632 mg (yield: 38%)) as a lightyellow solid.

31c Methyl3-{[4-methyl-5-(trans-4-{1-[trans-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methoxy}benzoate

The compound of Example 31(31b):[4-methyl-5-(trans-4-{1-[trans-4-(2-oxa-6-azaspiro[3.3]hepta-6-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methanol(100 mg, 0.227 mmol) was suspended in 1,4-dioxane (4 mL). To this,methyl 3-hydroxybenzoate (Tokyo Chemical Industry Co., Ltd., CatalogNumber: H0215) (104 mg, 0.681 mmol) and cyanomethylenetributylphosphorane (164 mg, 0.681 mmol) were added and the mixture wasstirred at 130° C. for 1 hour under microwave irradiation.

The reaction mixture was cooled to room temperature, and then purifiedby NH silica gel column chromatography [elution solvent methanol/ethylacetate=0/1-1/9 (V/V)], and then further purified by silica gel columnchromatography [elution solvent methanol/ethyl acetate=0/1-4/6 (V/V)].After the obtained crude product was dissolved in dichloromethane,diethyl ether was added. Then, the precipitated solid was collected byfiltration to obtain the title compound (66 mg (yield: 51%)) as a whitesolid.

Example 322-[trans-4-(4-{trans-4-[4-Methyl-5-({[3-(trifluoromethyl)cyclohexyl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-6-oxa-2-azaspiro[3.4]octane32a2-[trans-4-(4-{trans-4-[5-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-6-oxa-2-azaspiro[3.4]octane

The compound of Example 27(27c): benzyl2-[trans-4-(6-oxa-2-azaspiro[3.4]oct-2-yl)cyclohexyl]hydrazinecarboxylate (5 g, 13.9 mmol) was dissolved in ethanol (100 mL). To this,acetic acid (3.98 mL, 69.6 mmol) and a 10% palladium carbon catalyst(1.5 g) were added and the mixture was stirred at room temperature for17 hours under a hydrogen atmosphere.

Palladium-carbon was filtered off, and the filtrate was washed withethanol. The residue concentrated under reduced pressure was dissolvedin ethanol (80 mL). To this, a solution of the compound of Example30(30f):2-{trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}oxirane-2-carbaldehyde(5.84 g, 11.6 mmol) in ethanol (20 mL) was added, and the mixture wasstirred at room temperature for 19 hours, and then stirred at 80° C. for1 hour.

The reaction mixture was cooled to room temperature, then the residueobtained by concentration under reduced pressure was purified by NHsilica gel column chromatography [elution solvent: hexane/ethylacetate/methanol=2/8/0-0/95/5(V/V/V)] to obtain the title compound (6.19g (yield: 77%)) as a light brown solid.

32b[4-Methyl-5-(trans-4-{1-[trans-4-(6-oxa-2-azaspiro[3.4]oct-2-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methanol

The compound of Example 32(32a):2-[trans-4-(4-{trans-4-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-4-methyl-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-6-oxa-2-azaspiro[3.4]octane(6.19 g, 8.93 mmol) was dissolved in 1,4-dioxane (90 mL) and methanol(30 mL). To this, fluoride, polymer-supported (Sigma-AldrichCorporation, Catalog Number: 387789) (14.3 g, 35.5 mmol) was added, andthe mixture was stirred at 100° C. for 88 hours.

The reaction mixture was filtered, then the residue obtained byconcentration under reduced pressure was purified by silica gel columnchromatography [elution solvent: methanol/dichloromethane=1/9 (V/V)] toobtain the title compound (3.76 g (yield: 93%)) as a light brown solid.

32c2-[trans-4-(4-{trans-4-[4-Methyl-5-({[3-(trifluoromethyl)cyclohexyl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-6-oxa-2-azaspiro[3.4]octane

The compound of Example 32(32b):[4-methyl-5-(trans-4-{1-[trans-4-(6-oxa-2-azaspiro[3.4]oct-2-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methanol(150 mg, 0.33 mmol) and triethylamine (0.091 mL, 0.662 mmol) weredissolved in dichloromethane (5 mL). To this, methanesulfonyl chloride(0.038 mL, 0.498 mmol) was added under ice-cooling, and the mixture wasstirred under ice-cooling for 1 hour.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the mixture was extracted with dichloromethane. The organic layerwas washed with saturated saline, and dried over anhydrous sodiumsulfate. The resultant was concentrated under reduced pressure to obtain181 mg of[4-methyl-5-(trans-4-{1-[trans-4-(6-oxa-2-azaspiro[3.4]octa-2-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methylmethanesulfonate as a light brown solid.

3-(Trifluoromethyl)cyclohexanol (Enamine Ltd., Catalog Number::EN300-62207) (83 mg, 0.494 mmol) was dissolved in N,N-dimethylformamide(4 mL). To this, sodium hydride (55%) (22 mg, 0.504 mmol) was addedunder ice-cooling, and the mixture was stirred at room temperature for30 minutes. To the reaction mixture, a suspension of the obtained[4-methyl-5-(trans-4-{1-[trans-4-(6-oxa-2-azaspiro[3.4]octa-2-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methylmethanesulfonate (176 mg) in N,N-dimethylformamide (3 mL) was addedunder ice-cooling and the mixture was stirred at room temperature for 1hour.

Ice was added to the reaction mixture and the mixture was extracted withdichloromethane. The organic layer was washed with saturated saline, andthen dried over anhydrous sodium sulfate. After filtration, theresultant was concentrated under reduced pressure. The obtained residuewas purified by NH silica gel column chromatography [elution solvent:methanol/ethyl acetate=0/1-1/99 (V/V)], then by silica gel columnchromatography [elution solvent: methanol/dichloromethane=15/85 (V/V)]to obtain the title compound (77 mg (yield: 391)) as a white solid.

Example 331-{2-[4-Methyl-5-(trans-4-{1-[trans-4-(6-oxa-2-azaspiro[3.4]oct-2-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]ethyl}-3-(trifluoromethyl)pyridin-2(1H)-one33a4-Methyl-5-(trans-4-{1-[trans-4-(6-oxa-2-azaspiro[3.4]oct-2-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazole-3-carbaldehyde

The compound of Example 32(32b):[4-methyl-5-(trans-4-{1-[trans-4-(6-oxa-2-azaspiro[3.4]oct-2-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methanol (1 g, 2.2 mmol) was dissolved in dichloromethane (20 mL). Tothis, Dess-Martin periodinane (1.4 g, 3.3 mmol) was added underice-cooling and the mixture was stirred at room temperature for 17.5hours.

To the reaction mixture, saturated aqueous sodium bicarbonate and sodiumthiosulfate were sequentially added to the reaction mixture, and themixture was stirred and extracted with dichloromethane. The organiclayer was washed with saturated saline and then dried over anhydroussodium sulfate. The resultant was concentrated under reduced pressure toobtain the title compound (1.01 g (quantitative)) as a light brownsolid.

33b2-(trans-4-{4-[trans-4-(5-Ethenyl-4-methyl-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-1-yl}cyclohexyl)-6-oxa-2-azaspiro[3.4]octane

Methyltriphenylphosphonium bromide (Tokyo Chemical Industry Co., Ltd.,Catalog Number: M0779) (1.1 g, 3.09 mmol) was suspended intetrahydrofuran (7 mL). To this, potassium tert-butoxide (347 mg, 3.09mmol) was added under ice-cooling and the mixture was stirred for 20minutes. To the reaction mixture, a solution of the compound of Example33(33a): 4-methyl-5-(trans-4-{1-[trans-4-(6-oxa-2-azaspiro[3.4]octa-2-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazole-3-carbaldehyde(699 mg, 1.54 mmol) in tetrahydrofuran (21 mL) was added dropwise underice-cooling and the mixture was stirred at 0° C. for 1.5 hours.

Water was added to the reaction solution to stop the reaction. Then, tothe residue obtained by concentration under reduced pressure, water wasadded, and the mixture was extracted with dichloromethane. The organiclayer was washed with saturated saline and then dried over anhydroussodium sulfate. After filtration, the residue obtained by concentrationunder reduced pressure was purified by NH silica gel columnchromatography [elution solvent:hexane/dichloromethane/methanol=3/7/0-0/99/1 (V/V/V)] to obtain thetitle compound (647 mg (yield: 93%)) as a light brown solid.

33c1-{2-[4-Methyl-5-(trans-4-{1-[trans-4-(6-oxa-2-azaspiro[3.4]oct-2-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]ethyl}-3-(trifluoromethyl)pyridin-2(1H)-one

The compound of Example 33(33b):2-(trans-4-{4-[trans-4-(5-ethenyl-4-methyl-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-1-yl}cyclohexyl)-6-oxa-2-azaspiro[3.4]octane(25 mg, 0.06 mmol) and 3-(trifluoromethyl)pyridin-2(1H)-one (CASRegistry Number: 22245-83-6, WO2007126765) (45 mg, 0.28 mmol) weresuspended by adding acetonitrile (1 mL). The mixture was stirred at 120°C. for 1 hour under microwave irradiation.

The residue obtained by concentrating the reaction mixture under reducedpressure was purified by silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=8/92-1/9 (V/V)] to obtain the crudeproduct (25 mg).

Similarly, the compound of Example 33(33b):2-(trans-4-{4-[trans-4-(5-ethenyl-4-methyl-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-pyrazol-1-yl}cyclohexyl)-6-oxa-2-azaspiro[3.4]octane(100 mg, 0.22 mmol) and 3-(trifluoromethyl)pyridin-2(1H)-one (CASRegistry Number: 22245-83-6, WO2007126765) (181 mg, 1.11 mmol) wereadded to acetonitrile (4 mL) and suspended. The mixture was stirred at120° C. for 1 hour under microwave irradiation.

The residue obtained by concentrating the reaction mixture under reducedpressure was purified by silica gel column chromatography [elutionsolvent: methanol/ethyl acetate=8/92-1/9 (V/V)]. The obtained crudeproduct was combined with the previously obtained crude product (25 mg)and triturated with ethyl acetate to obtain the title compound (131 mg(yield: 77%)) as a white solid.

Example 341-Methyl-4-{5-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine34a tert-Butyl4-{5-[4-(methoxycarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

tert-Butyl4-({2-[4-(methoxycarbonyl)benzoyl]hydrazinyl}carbonyl)piperidine-1-carboxylate(CAS Registry Number: 208537-78-4, WO199823637) (500 mg, 1.23 mmol) wasdissolved in tetrahydrofuran (5 mL). To this,(methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (TokyoChemical Industry Co., Ltd., Catalog Number: M1279) (647 mg, 2.71 mmol)was added, and the mixture was stirred at 120° C. for 15 minutes undermicrowave irradiation.

To the reaction mixture, water was added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated salineand then dried over anhydrous sodium sulfate. To the residue obtained byconcentration under reduced pressure, ethyl acetate and hexane wereadded, and the precipitated solid was collected by filtration to obtainthe title compound (380 mg (yield: 79%)) as a white solid.

34b4-{5-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-1,3,4-oxadiazol-2-yl}benzoicacid

The compound of Example 34(34a): tert-Butyl4-{5-[4-(methoxycarbonyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate(300 mg, 0.77 mmol) was dissolved in methanol (1.5 mL) andtetrahydrofuran (1.5 mL). To this, a solution of sodium hydroxide (155mg, 3.87 mmol) in water (1.5 mL) was added under ice-cooling, and themixture was stirred at room temperature for 2 hours.

After concentration under reduced pressure, the mixture was acidifiedwith 1N hydrochloric acid and extracted with dichloromethane. Theorganic layer was washed with saturated saline and then dried overanhydrous sodium sulfate. The resultant was concentrated under reducedpressure to obtain the title compound (250 mg (yield: 86%)) as a whitesolid.

34c tert-Butyl4-{5-[4-(methylcarbamoyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

The compound of Example 34(34b):4-{5-[1-(tert-Butoxycarbonyl)piperidin-4-yl]-1,3,4-oxadiazol-2-yl}benzoicacid (240 mg, 0.64 mmol) was dissolved in N,N-dimethylformamide (0.6mL). To this, triethylamine (0.27 mL, 1.93 mmol), methylaminehydrochloride (Tokyo Chemical Industry Co., Ltd., Catalog Number: M0138)(52 mg, 0.77 mmol), 3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (44 mg, 0.32mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (185mg, 0.96 mmol) were added and the mixture was stirred at roomtemperature for 4 hours.

The reaction mixture was diluted with dichloromethane. To this,saturated aqueous sodium bicarbonate was added, and the mixture wasextracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate. The residue obtained by concentration underreduced pressure was purified by silica gel column chromatography[elution solvent: methanol/dichloromethane=0/1-1/9 (V/V)] to obtain thetitle compound (250 mg (yield: 100)) as a white solid.

34d tert-Butyl4-{5-[4-(methylcarbamothioyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

The compound of Example 34(34c): tert-butyl4-{5-[4-(methylcarbamoyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate(240 mg, 0.621 mmol) was dissolved in tetrahydrofuran (6.2 mL). To this,Lawesson's reagent (276 mg, 0.683 mmol) was added, and the mixture wasstirred at room temperature for 1 hour and allowed to stand stillovernight.

The residue obtained by concentration under reduced pressure waspurified by silica gel column chromatography [elution solvent:methanol/dichloromethane=0/1-1/9 (V/V)] to obtain the title compound(246 mg (yield: 98%)) as a light yellow solid.

34e tert-Butyl4-{5-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

The compound of Example 34(34d): tert-Butyl4-{5-[4-(methylcarbamothioyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate(230 mg, 0.571 mmol) was dissolved in tetrahydrofuran (1.1 mL). To this,methyl iodide (122 mg, 0.857 mmol) and potassium carbonate (158 mg, 1.14mmol) were added, and the mixture was stirred at room temperature for 1hour and then at 50° C. for 1 hour.

Insoluble matters were removed by filtration, and the filtrate wasconcentrated under reduced pressure. The obtained residue was dissolvedby adding tetrahydrofuran (1.1 mL). To this, methyl iodide (811 mg, 5.71mmol) was added, and the mixture was stirred at 70° C. for 3 hours.

Insoluble matters were removed by filtration, and the filtrate wasconcentrated under reduced pressure to obtain the crude product oftert-butyl 4-(5-{4-[(methylimino)(methylsulfanyl)methyl]phenyl}-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate(275 mg).

The obtained crude product (130 mg) was dissolved in ethanol (0.62 mL)and the compound of Example 1(1a):2-[3-(trifluoromethyl)phenoxy]acetohydrazide (87.7 mg, 0.375 mmol) wasadded and the mixture was stirred at 90° C. for 3 hours. To the reactionmixture, the compound of Example 1(1a):2-[3-(trifluoromethyl)phenoxy]acetohydrazide (87.7 mg, 0.375 mmol) wasadded and the mixture was stirred at 90° C. for 3 hours.

The reaction mixture was diluted with dichloromethane. To this, asaturated aqueous ammonium chloride solution was added, and the mixturewas extracted with dichloromethane. The organic layer was washed withsaturated aqueous sodium bicarbonate and then dried over anhydroussodium sulfate. The residue obtained by concentration under reducedpressure was purified by silica gel column chromatography [elutionsolvent: methanol/dichloromethane=0/1-1/19 (V/V)] to obtain the titlecompound (40 mg (yield: 22%)) as a white solid.

34f4-{5-[4-(4-Methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine

To a solution of the compound of Example 34(34e): tert-butyl4-{5-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate(40 mg, 0.0684 mmol) in dichloromethane (0.27 mL), trifluoroacetic acid(0.157 mL, 2.05 mmol) was added, and the mixture was stirred at roomtemperature for 2 hours.

To the residue obtained by concentration under reduced pressure,saturated aqueous sodium bicarbonate was added, and the mixture wasextracted with chloroform. The organic layer was washed with saturatedsaline, and dried over anhydrous sodium sulfate. The resultant wasconcentrated under reduced pressure to obtain the title compound (30 mg(yield: 90%)) as a white solid.

34g1-Methyl-4-{5-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine

To a solution of the compound of Example 34(34f)4-{5-[4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine(25 mg, 0.0516 mmol) in dichloromethane (0.21 mL), a formaldehydesolution (37%) (0.011 mL, 0.155 mmol) was added, and the mixture wasstirred at room temperature for 5 minutes. To the reaction mixture,sodium triacetoxyborohydride (95%) (54.7 mg, 0.258 mmol) was added, andthe mixture was stirred at room temperature for 1 hour.

To the reaction mixture, saturated aqueous sodium bicarbonate was added,and the reaction mixture was extracted with dichloromethane. The organiclayer was washed with saturated saline, and dried over anhydrous sodiumsulfate. To the crude product obtained by concentration under reducedpressure, ethyl acetate was added, and the precipitated solid wascollected by filtration to obtain the title compound (15 mg (yield:58%)) as a light yellow solid.

Example 353-(trans-4-{5-[(2S,5R)-5-(Azetidin-1-yl)tetrahydro-2H-pyran-2-yl]-1,2-oxazol-3-yl}cyclohexyl)-5-[(3-chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazole35a Methyltrans-4-{5-[(3-chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexanecarboxylate

The compound of Example 19(19c): methyltrans-4-[(methylimino)(methylsulfanyl)methyl]cyclohexane carboxylate(10.1 g, 44 mmol) was dissolved in ethanol (50 mL). To this,2-(3-chlorophenoxy)acetohydrazide (CAS Registry Number: 52094-93-6,Bioorganic & Medicinal Chemistry 19 (2011) 211-220) (8.41 g, 41.9 mmol)was added and the mixture was stirred at 100° C. for 5 hours.

To the residue obtained by concentration under reduced pressure,isopropyl alcohol was added, and the precipitated solid was collected byfiltration to obtain the title compound (9.55 g (yield: 63%)) as a whitesolid.

35b(trans-4-{5-[(3-Chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexyl)methanol

The compound of Example 35(35a): methyltrans-4-{5-[(3-chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexanecarboxylate(9.55 g, 26.3 mmol) was dissolved in tetrahydrofuran (160 mL). To this,a lithium aluminium hydride-tetrahydrofuran solution (2.5 M, 8 mL) wasadded under ice-cooling, and the mixture was stirred at room temperaturefor 1 hour and then at 60° C. for 1 hour.

To the reaction mixture, water (1 mL), a 1N aqueous sodium hydroxidesolution (3 mL), and water (1 mL) were sequentially added underice-cooling. The residue obtained by concentration under reducedpressure was purified by silica gel column chromatography [elutionsolvent: hexane/ethyl acetate=3/2-0/1, methanol/ethyl acetate=1/1 (V/V)]to obtain the title compound (5.5 g (yield: 62%)) as a white solid.

35ctrans-4-{5-[(3-Chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexanecarbaldehyde

The compound of Example 35(35b):(trans-4-{5-[(3-chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexyl)methanol(1 g, 2.98 mmol) was dissolved in dichloromethane (10 mL) and dimethylsulfoxide (10 mL). To this, diisopropylethylamine (2.2 mL, 12.6 mmol)and pyridine-sulfur-trioxide complex (2.07 g, 13 mmol) were added underice-cooling and the mixture was stirred for 1.5 hours.

To the reaction mixture, dichloromethane and water were added, themixture was extracted with dichloromethane. The organic layer was washedwith water and dried over anhydrous sodium sulfate. The resultant wasconcentrated under reduced pressure to obtain the title compound (1.3 g(quantitative)) as a colorless oily substance.

35d1-(trans-4-{5-[(3-Chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexyl)-N-hydroxymethanimine

The compound of Example 35(35c):trans-4-{5-[(3-chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexanecarbaldehyde(1.3 g, 2.98 mmol) was dissolved in methanol (15 mL). To this,hydroxylamine hydrochloride (620 mg, 8.92 mmol) and sodium acetate (740mg, 9.02 mmol) were added and the mixture was stirred at roomtemperature for 2 hours.

To the reaction mixture, ethyl acetate and water were added, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated saline and dried over anhydrous sodium sulfate.The residue obtained by concentration under reduced pressure, isopropylalcohol was added, and the precipitated solid was filtered to obtain thetitle compound (1.1 g (quantitative)) as a white solid.

35e tert-Butyl{(3R,6S)-6-[3-(trans-4-{5-[(3-chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexyl)-1,2-oxazol-5-yl]tetrahydro-2H-pyran-3-yl}carbamate

The compound of Example 35(35d):1-trans-4-{5-[3-chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexyl)-N-hydroxymethanaimine(430 mg, 1.23 mmol) was dissolved in N,N-dimethylformamide (10 mL). Tothis, N-chlorosuccinimide (180 mg, 1.35 mmol) was added and stirred at50° C. for 1.5 hours. To the reaction mixture, a solution of tert-butyl[(3R,6S)-6-ethynyltetrahydro-2H-pyran-3-yl]carbamate (CAS RegistryNumber: 881657-41-6, WO2006032466) (8.41 g, 41.9 mmol) and triethylamine(1.7 mL, 12.2 mmol) in N,N-dimethylformamide (3 mL) was added, and themixture was stirred at room temperature for 30 minutes and then at 60°C. for 1.5 hours.

To the reaction mixture, ethyl acetate and tetrahydrofuran were added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with diluted hydrochloric acid, water and saturated saline, andthe mixture was dried over anhydrous sodium sulfate. The residueobtained by concentration under reduced pressure was purified by silicagel column chromatography [elution solvent: ethylacetate/dichloromethane=3/7-1/0 (V/V)] to obtain the title compound (180mg (yield: 25%)) as a white solid.

35f(3R,6S)-6-[3-(trans-4-{5-[(3-Chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexyl)-1,2-oxazol-5-yl]tetrahydro-2H-pyran-3-amine

The compound of Example 35(35e):tert-butyl{(3R,6S)-6-[3-(trans-4-{5-[(3-chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexyl)-1,2-oxazol-5-yl]tetrahydro-2H-pyran-3-yl}carbamate(180 mg, 0.315 mmol) was dissolved in methanol (2 mL). To this, 4Nhydrochloric acid-1,4-dioxane (4 mL, 16 mmol) was added, and the mixturewas stirred at room temperature for 1 hour.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent:methanol/ethyl acetate=0/1-3/7 (V/V)] to obtain the title compound (134mg (yield: 90%)) as a white solid.

35g3-(trans-4-{5-[(2S,5R)-5-(Azetidin-1-yl)tetrahydro-2H-pyran-2-yl]-1,2-oxazol-3-yl}cyclohexyl)-5-[(3-chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazole

The compound of Example 35(35f):(3R,6S)-6-[3-(trans-4-{5-[(3-chlorophenoxy)methyl]-4-methyl-4H-1,2,4-triazol-3-yl}cyclohexyl)-1,2-oxazol-5-yl]tetrahydro-2H-pyran-3-amine(134 mg, 0.284 mmol) was dissolved in acetonitrile (15 mL). To this,1,3-dibromopropane (Tokyo Chemical Industry Co., Ltd., Catalog Number:D0202) (229 mg, 1.13 mmol) and potassium carbonate (152 mg, 1.1 mmol)were added, and the mixture was stirred at 90° C. for 3 hours, and thenat 80° C. for 17 hours.

The residue obtained by concentration under reduced pressure waspurified by NH silica gel column chromatography [elution solvent:methanol/ethyl acetate=0/1-15/85 (V/V)] to obtain the title compound(41.3 mg (yield: 28%)) as a white solid.

Example 368-Methyl-3-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene36a tert-Butyl3-[trans-4-(methylcarbamoyl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate

Methyl trans-4-[chloro(hydroxyimino)methyl]cyclohexanecarboxylate (CASRegistry Number: 1346450-09-6, WO2013050334) (1.5 g, 6.83 mmol) wasdissolved in dichloromethane (50 mL). To this, tert-butyl4-methylidenepiperidine-1-carboxylate (Wako Pure Chemical Industries,Ltd. Catalog Number: 353-23543) (2.02 g, 10.3 mmol) and sodium hydrogencarbonate (1.15 g, 13.7 mmol) were added, and the mixture was stirred at30° C. for 16 hours.

The reaction mixture was filtered, and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography [elution solvent: ethyl acetate/petroleum ether=1/30(V/V)] to obtain tert-Butyl3-[trans-4-(methoxycarbonyl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate(2 g) as a white solid.

To a solution of the obtained tert-butyl3-[trans-4-(methoxycarbonyl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate(1 g, 2.63 mmol) in methanol (10 mL)/water (2 mL), lithium hydroxidemonohydrate (221 mg, 5.26 mmol) was added, and the mixture was stirredat 30° C. for 16 hours.

To the residue obtained by concentration under reduced pressure, waterwas added, and the mixture was extracted with ethyl acetate. The aqueouslayer was adjusted with 2N hydrochloric acid to about pH=6 and extractedwith ethyl acetate. The combined organic layer was dried over anhydroussodium sulfate. The resultant was concentrated under reduced pressure toobtaintrans-4-[8-(tert-butoxycarbonyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl]cyclohexanecarboxylicacid (950 mg) as a white solid.

To a solution of the obtainedtrans-4-[8-(tert-butoxycarbonyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl]cyclohexanecarboxylicacid (1.7 g, 4.64 mmol) and methylamine hydrochloride (849 mg, 12.6mmol) in dichloromethane (20 mL), diisopropylethylamine (1.8 g, 13.9mmol) and methylamine hydrochloride (1.76 g, 4.64 mmol) were added, andthe mixture was stirred at 30° C. for 16 hours.

To the reaction mixture, water was added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated saline,and dried over anhydrous sodium sulfate. The residue obtained byconcentration under reduced pressure was purified by silica gelchromatography [elution solvent: ethyl acetate/petroleum ether=1/10-1/1,methanol/dichloromethane=1/10 (V/V)], and triturated with petroleumether (30 mL) to obtain the title compound (2.3 g (yield: 76%)) as awhite solid.

36b8-Methyl-3-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene

The compound of Example 36(36a): tert-butyl3-[trans-4-(methylcarbamoyl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate(1.8 g, 4.74 mmol) was dissolved in tetrahydrofuran (40 mL). To this,Lawesson's reagent (2.88 g, 7.11 mmol) was added and the mixture wasstirred at 60° C. for 10 hours.

After the reaction temperature had returned to room temperature, theresidue obtained by concentration under reduced pressure was purified bysilica gel column chromatography [elution solvent:methanol/dichloromethane=1/100-1/30 (V/V)], then purified by thin layersilica gel chromatography [developing solvent:methanol/dichloromethane=1/20 (V/V)] to obtain tert-butyl3-[trans-4-(methylcarbamothioyl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate(410 mg) as a white solid.

To a solution of the obtained tert-butyl3-[trans-4-(methylcarbamothioyl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate(260 mg, 0.657 umol) in tetrahydrofuran (10 mL), potassium carbonate(273 mg, 1.97 mmol) and methyl iodide (933 mg, 6.57 mmol) were added,and the mixture was stirred at 80° C. for 16 hours.

To the residue obtained by concentration under reduced pressure, waterwas added, and the mixture was extracted with dichloromethane. Theorganic layer was washed with saturated saline, and dried over anhydroussodium sulfate. The resultant was concentrated under reduced pressure toobtain tert-butyl 3-{trans-4-[(methylimino)(methylsulfanyl)methyl]cyclohexyl}-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-carboxylate(300 mg) as a crude product.

The obtained crude product of tert-butyl3-{trans-4-[(methylimino)(methylsulfanyl)methyl]cyclohexyl}-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-carboxylate(200 mg) was dissolved in ethanol (5 mL). To this, the compound ofExample 4(4a): (2R)-2-[3-(propan-2-yl)phenoxy]propanehydrazide (163 mg,0.732 mmol) was added, and the mixture was stirred at 80° C. for 16hours.

The residue obtained by concentration under reduced pressure waspurified by high performance liquid chromatography to obtain tert-butyl3-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate(140 mg, (yield: 51%)) as a white solid.

To a solution of the obtained tert-butyl3-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-carboxylate(140 mg, 0.247 mmol) in dichloromethane (4 mL), 4N hydrochloricacid-1,4-dioxane (0.5 mL, 2 mmol) was added, and the mixture was stirredat 30° C. for 2 hours.

The resultant was concentrated under reduced pressure to obtain3-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene(124 mg) as a crude product.

The obtained crude product of3-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5] dec-2-ene (124 mg) was dissolved in tetrahydrofuran (4 mL) andN,N-dimethylformamide (2 mL). To this, sodium bicarbonate (62.2 mg,0.741 mmol) and a formaldehyde solution (37%) (111 mg, 1.23 mmol) wasadded and the mixture was stirred at 30° C. for 1 hour. To this,triacetoxyborohydride (157 mg, 0.741 mmol) was added and the mixture wasstirred at 30° C. for 15 hours.

The residue obtained by concentration under reduced pressure waspurified by high performance liquid chromatography to obtain the titlecompound (44.7 mg (yield: 8.3%)) as a white solid.

The analysis results of the compounds of Examples by powder X-raydiffraction are shown below.

Analysis conditions:

Machine model: Rigaku Rint TTR-III

Sample holder: Non-reflective sample holder

Samples: Appropriate amount

X-ray generation conditions: 50 kV, 300 mA

Wavelength: 1.54 Å (Copper Kα Ray)

Scan Speed: 20°/min

Scan Range: 2-40°

Sampling width: 0.02°

Analysis procedures: Several mg of the test substance was collected witha spatula, placed on a non-reflective sample holder, and flattened withmedicine wrapping paper. Thereafter, the peak pattern was analyzed underthe above conditions.

Example 4

Table 2 shows peaks of relative intensity 4 or more when the maximumpeak intensity is 100 in the diffraction pattern of powder X-raydiffraction (CuKα, λ=1.54 Å, scanning speed=20°/min) in FIG. 1.

TABLE 2 Peak Relative Peak Relative Number 2θ d Value Intensity Number2θ d Value Intensity 1  3.94 22.41  97 5 16.20 5.47 13 2  4.10 21.53 1006 18.42 4.81 11 3  8.34 10.59  17 7 19.46 4.56 11 4 12.58  7.03  4 822.32 3.98  7

Example 8

Table 3 shows peaks of relative intensity 4 or more when the maximumpeak intensity is 100 in the diffraction pattern of powder X-raydiffraction (CuKα, λ=1.54 Å, scanning speed=20°/min) in FIG. 2.

TABLE 3 Peak Relative Peak Relative Number 2θ d Value Intensity Number2θ d Value Intensity 1  3.80 23.23 100 5 19.76 4.49 21 2 16.38  5.41  226 21.18 4.19 19 3 18.02  4.92  41 7 22.74 3.91 20 4 18.56  4.78  36

Example 20

Table 4 shows peaks of relative intensity 4 or more when the maximumpeak intensity is 100 in the diffraction pattern of powder X-raydiffraction (CuKα, λ=1.54 Å, scanning speed=20°/min) in FIG. 3.

TABLE 4 Peak Relative Peak Relative Number 2θ d Value Intensity Number2θ d Value Intensity 1 13.52 6.54 20  6 19.16 4.63  89 2 15.74 5.63 29 7 20.40 4.35 100 3 17.18 5.16 40  8 20.76 4.28  53 4 17.78 4.98 38  921.96 4.04  26 5 18.16 4.88 72 10 27.22 3.27  18

Example 24

Table 5 shows peaks of relative intensity 4 or more when the maximumpeak intensity is 100 in the diffraction pattern of powder X-raydiffraction (CuKα, λ=1.54 Å, scanning speed=20°/min) in FIG. 4.

TABLE 5 Peak Relative Peak Relative Number 2θ d Value Intensity Number2θ d Value Intensity 1  3.30 26.75 42  6 17.90 4.95  38 2 13.36  6.62 16 7 18.88 4.70  54 3 15.46  5.73 23  8 20.44 4.34 100 4 16.84  5.26 29  921.78 4.08  17 5 17.54  5.05 30 10 26.90 3.31  17

Example 25

Table 6 shows peaks of relative intensity 4 or more when the maximumpeak intensity is 100 in the diffraction pattern of powder X-raydiffraction (CuKα, λ=1.54 Å, scanning speed=20°/min) in FIG. 5.

TABLE 6 Peak Relative Peak Relative Number 2θ d Value Intensity Number2θ d Value Intensity 1 13.16 6.72 20  6 19.00 4.67  88 2 15.80 5.60 24 7 20.26 4.38 100 3 16.48 5.37 30  8 20.82 4.26  47 4 17.76 4.99 69  921.38 4.15  22 5 18.08 4.90 55 10 27.86 3.20  25

Example 27

Table 7 shows peaks of relative intensity 4 or more when the maximumpeak intensity is 100 in the diffraction pattern of powder X-raydiffraction (CuKα, λ=1.54 Å, scanning speed=20°/min) in FIG. 6.

TABLE 7 Peak Relative Peak Relative Number 2θ d Value Intensity Number2θ d Value Intensity 1 14.16 6.25 58  6 19.48 4.55 100 2 16.72 5.30 59 7 19.96 4.44  51 3 17.36 5.10 43  8 20.88 4.25  57 4 18.22 4.87 75  921.58 4.11  42 5 18.64 4.76 51 10 21.82 4.07  41

Example 31

Table 8 shows peaks of relative intensity 4 or more when the maximumpeak intensity is 100 in the diffraction pattern of powder X-raydiffraction (CuKα, λ=1.54 Å, scanning speed=20°/min) in FIG. 7.

TABLE 8 Peak Relative Peak Relative Number 2θ d Value Intensity Number2θ d Value Intensity 1 15.38 5.76 26  6 19.18 4.62 100 2 17.64 5.02 49 7 20.18 4.40  39 3 17.92 4.95 36  8 20.70 4.29  30 4 18.36 4.83 27  922.96 3.87  42 5 18.66 4.75 36 10 23.76 3.74  32

In the following tables, the structural formula of the compoundsdescribed in the Examples and physicochemical data thereof arecollectively shown.

The abbreviations listed below are used.

Bn: benzyl groupEt: ethyl groupMe: methyl groupiPr: i-propyl grouptBu: t-butyl groupPh: phenyl groupCbz: benzyloxycarbonyl groupBoc: t-butoxycarbonyl groupTBDMS: t-butyldimethylsilyl groupTBDPS: t-butyldiphenylsilyl group

TABLE 9 Ex- ample No. Structural formula Physicochemical data 1(1a)

1H NMR (CDCl₃) δ(ppm) 3.94 (br s, 2H) 4.62 (s, 2H) 7.09 (dd, J = 8.5,2.7 Hz, 1H) 7.16 (s, 1H) 7.31 (d, J = 7.8 Hz, 1H) 7.46 (t, J = 8.1 Hz,1H) 7.69 (br s, 1H). 1(1b)

1H NMR (CDCl₃) δ(ppm) 1.53 (s, 9H) 3.36 (d, J = 4.9 Hz, 3H) 6.62 (br s,1H) 7.39 (d, J = 8.3 Hz, 2H) 7.64 (br s, 1H) 7.75 (d, J = 8.6 Hz, 2H).1(1c)

1H NMR (CDCl₃) δ(ppm) 1.54 (s, 9H) 3.76 (s, 3H) 5.37 (s, 2H) 6.65 (s,1H) 7.27-7.32 (m, 3H) 7.45 (t, J = 7.3 Hz, 1H) 7.51-7.55 (m, 2H)7.58-7.63 (m, 2H). 1(1d)

1H NMR (CDCl₃) δ(ppm) 3.75 (s, 3H) 3.94 (br s, 2H) 5.36 (s, 2H)6.76-6.79 (m, 2H) 7.25-7.32 (m, 3H) 7.42-7.47 (m, 3H). 1(1e)

1H NMR (CDCl₃) δ(ppm) 3.85 (s, 3H) 5.45 (s, 2H) 7.20-7.35 (m, 5H) 7.48(t, J = 7.9 Hz, 1H) 7.68 (d, J = 8.5 Hz, 2H). 1(1f)

1H NMR (DMSO-d₆) δ(ppm) 1.42 (s, 9H) 1.47-1.62 (m, 2H) 1.96-2.04 (m, 2H)2.86-3.03 (m, 4H) 3.80 (s, 3H) 3.97-4.05 (m, 1H) 5.53 (s, 2H) 7.38 (d, J= 7.9 Hz, 1H) 7.44-7.51 (m, 2H) 7.60 (t, J = 7.9 Hz, 1H) 7.99 (d, J =8.5 Hz, 2H) 8.10 (d, J = 8.5 Hz, 2H) 8.79 (s, 1H). 1(1g)

1H NMR (CDCl₃) δ(ppm) 1.23-1.27 (m, 1H) 1.62- 1.75 (m, 2H) 2.09-2.16 (m,2H) 2.77-2.85 (m, 2H) 2.97-3.06 (m, 1H) 3.18-3.24 (m, 2H) 3.84 (s, 3H)5.41 (s, 2H) 7.28-7.33 (m, 3H) 7.46 (t, J = 7.9 Hz, 1H) 7.79 (s, 1H)7.86 (d, J = 8.5 Hz, 2H) 7.94 (d, J = 8.5 Hz, 2H). 1(1h)

1H NMR (CDCl₃) δ(ppm) 1.52-1.60 (m, 2H) 1.78- 1.89 (m, 2H) 2.10-2.19 (m,3H) 2.36 (s, 3H) 2.83- 3.03 (m, 2H) 3.84 (s, 3H) 5.41 (s, 2H) 7.28-7.33(m, 3H) 7.46 (t, J = 7.9 Hz, 1H) 7.79 (s, 1H) 7.85 (d, J = 8.5 Hz, 2H)7.93 (d, J = 7.6 Hz, 2H). MS (APCI) m/z: 498 [M + H]⁺. 2(2a)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.8 Hz, 6H) 2.80-2.93 (m, 1H) 3.81(s, 3H) 4.64 (s, 2H) 6.69 (dd, J = 8.1, 2.7 Hz, 1H) 6.82 (t, J = 2.2 Hz,1H) 6.85-6.90 (m, 1H) 7.21 (t, J = 7.8 Hz, 1H).

TABLE 10 Ex - ample No. Structural formula Physicochemical data 2(2b)

1H NMR (CDCl₃) δ(ppm) 1.25 (d, J = 6.8 Hz, 6H) 2.85-2.94 (m, 1H) 3.93(br s, 2H) 4.59 (s, 2H) 6.71 (d, J = 7.8 Hz, 1H) 6.79 (br d, J = 2.0 Hz,1H) 6.92 (br d, J = 7.8 Hz 1H) 7.22-7.31 (m, 1H) 7.76 (br s, 1H). 2(2c)

1H NMR (CDCl₃) δ(ppm) 1.45 (s, 9H) 3.02 (d, J = 5.4 Hz, 3H) 6.77 (br s,1H) 7.85 (br s, 1H) 8.00 (br d, J = 7.8 Hz, 1H) 8.14 (d, J = 8.8 Hz, 1H)8.46 (d, J = 2.4 Hz, 1H). 2(2d)

1H NMR (CDCl₃) δ(ppm) 1.54 (s, 9H) 3.38 (d, J = 5.4 Hz, 3H) 6.67 (br s,1H) 7.92 (dd, J = 8.8, 2.4 Hz, 1H) 8.45 (d, J = 2.4 Hz, 1H) 8.65 (d, J =8.8 Hz, 1H) 10.00 (br s, 1H). 2(2e)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.8 Hz, 6H) 1.55 (s, 9H) 2.82-2.98(m, 1H) 4.13 (s, 3H) 5.33 (s, 2H) 6.64 (s, 1H) 6.86-6.95 (m, 3H) 7.24(t, J = 7.5 Hz, 1H) 8.01 (br d, J = 7.3 Hz, 1H) 8.24 (d, J = 8.8 Hz, 1H)8.59 (d, J = 2.4 Hz, 1H). 2(2f)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 7.3 Hz, 6H) 2.83-2.95 (m, 1H) 3.92(br s, 2H) 4.10 (s, 3H) 5.31 (s, 2H) 6.84-6.94 (m, 3H) 7.03-7.13 (m, 1H)7.21-7.25 (m, 1H) 8.04-8.12 (m, 2H). 2(2g)

1H NMR (CDCl₃) δ(ppm) 1.25 (d, J = 6.8 Hz, 6H) 1.49 (s, 9H) 1.50-1.55(m, 2H) 1.64-1.75 (m, 2H) 2.08-2.15 (m, 2H) 2.86-2.98 (m, 3H) 3.02-3.10(m, 1H) 4.22 (s, 3H) 5.37 (s, 2H) 6.91-6.93 (m, 3H) 7.22-7.27 (m, 1H)7.80- 7.82 (m, 1H) 8.18-8.23 (m, 1H) 8.53 (d, J = 8.8 Hz, 1H) 9.09-9.12(m, 1H). 2(2h)

1H NMR (CDCl₃) δ(ppm) 1.25 (d, J = 7.3 Hz, 6H) 1.63-1.75 (m, 2H)2.09-2.16 (m, 2H) 2.78- 2.85 (m, 2H) 2.87-2.93 (m, 1H) 2.98-3.06 (m, 1H)3.17-3.24 (m, 2H) 4.21 (s, 3H) 5.37 (s, 2H) 6.89-6.95 (m, 3H) 7.23-7.27(m, 1H) 7.80 (s, 1H) 8.18-8.22 (m, 1H) 8.51-8.54 (m, 1H) 9.10-9.13 (m,1H). 2(2i)

1H NMR (CDCl₃) δ(ppm) 1.25 (d, J = 6.8 Hz, 6H) 1.76-1.87 (m, 2H)2.09-2.18 (m, 4H) 2.34 (s, 3H) 2.84-3.00 (m, 4H) 4.21 (s, 3H) 5.37 (s,2H) 6.87-6.97 (m, 3H) 7.22-7.29 (m, 1H) 7.80 (s, 1H) 8.20-8.21 (m, 1H)8.51-8.53 (m, 1H) 9.11 (s, 1H). MS (APCI) m/z: 473 [M + H]⁺. 3(3a)

1H NMR (CDCl₃) δ(ppm) 1.13-1.21 (m, 2H) 1.44 (s, 9H) 1.68-1.76 (m, 1H)1.92-2.02 (m, 2H) 2.08-2.16 (m, 2H) 2.46-2.51 (m, 1H) 3.19 (d, J = 4.9Hz, 3H) 3.42-3.46 (m, 1H) 3.79-3.90 (m, 1H) 4.38 (br s, 1H) 7.30 (br s,1H).

TABLE 11 Ex- ample No. Structural formula Physicochemical data 3(3b)

1H NMR (CDCl₃) δ(ppm) 1.08-1.21 (m, 2H) 1.44 (s, 9H) 1.52-1.92 (m, 3H)2.13-2.16 (m, 2H) 2.17-2.26 (m, 1H) 2.42 (s, 3H) 2.72-2.82 (m, 0.3H)3.17 (s, 2H) 3.26 (s, 1H) 3.34-3.50 (m, 1H) 3.77-3.91 (m, 0.7H)4.29-4.43 (m, 1H). 3(3c)

1H NMR (CDCl₃) δ(ppm) 1.19-1.30 (m, 8H) 1.46 (s, 9H) 1.83-1.94 (m, 2H)1.98-2.06 (m, 2H) 2.19 (br d, J = 12.2 Hz, 2H) 2.59 (tt, J = 12.0, 3.4Hz, 1H) 2.82- 2.94 (m, 1H) 3.45-3.60 (m, 1H) 3.65 (s, 3H) 4.43 (br s,1H) 5.24 (s, 2H) 6.84-6.91 (m, 3H) 7.23 (t, J = 7.6 Hz, 1H). 3(3d)

1H NMR (CDCl₃) δ(ppm) 1.23 (d, J = 6.8 Hz, 6H) 1.33-1.42 (m, 2H)1.78-1.87 (m, 2H) 1.98-2.05 (m, 2H) 2.06-2.13 (m, 2H) 2.45-2.68 (m, 3H)2.84-2.99 (m, 2H) 3.65 (s, 3H) 5.22 (s, 2H) 6.83-6.90 (m, 3H) 7.21-7.25(m, 1H). 3(3e)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.8 Hz, 6H) 1.48 (dq, J = 2.8, 12.8Hz, 2H) 1.85-1.91 (m, 2H) 2.07-2.10 (m, 2H) 2.20 (dd, J = 13.2, 2.9 Hz,2H) 2.63-2.65 (m, 1H) 2.86-2.91 (m, 1H) 3.42-3.44 (m, 1H) 3.66 (s, 3H)5.24 (s, 2H) 6.87-6.88 (m, 3H) 7.23 (t, J = 7.6 Hz, 1H). 3(3f)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.8 Hz, 6H) 1.47 (s, 9H) 1.90-1.92(m, 2H) 2.00-2.09 (m, 7H) 2.21-2.22 (m, 2H) 2.42-2.43 (m, 2H) 2.76-2.85(m, 1H) 2.85-2.93 (m, 1H) 3.36-3.38 (m, 2H) 3.70 (s, 3H) 3.87-3.89 (m,2H) 4.51-4.55 (m, 1H) 5.26 (s, 2H) 6.87-6.89 (m, 3H) 7.23-7.24 (m, 1H)7.50 (s, 1H). 3(3g)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.8 Hz, 6H) 1.48 (s, 9H) 2.00-2.25(m, 10H) 2.43-2.44 (m, 2H) 2.77-2.80 (m, 1H) 2.85-2.93 (m, 1H) 3.27 (s,2H) 3.69 (s, 3H) 3.99-4.01 (m, 2H) 4.52-4.56 (m, 1H) 5.26 (s, 2H)6.87-6.89 (m, 3H) 7.23-7.24 (m, 1H) 7.60 (s, 1H). 3(3h)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.3 Hz, 6H) 2.01-2.09 (m, 4H)2.19-2.34 (m, 6H) 2.35 (s, 3H) 2.42-2.48 (m, 4H) 2.72-2.80 (m, 3H)2.85-2.93 (m, 1H) 3.69 (s, 3H) 4.52-4.54 (m, 1H) 5.26 (s, 2H) 6.87-6.89(m, 3H) 7.23-7.26 (m, 1H) 7.58 (s, 1H). MS (APCI) m/z: 496 [M + H]⁺.4(4a)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.8 Hz, 6H) 1.59 (d, J = 6.8 Hz, 3H)2.83-2.92 (m, 1H) 3.85 (d, J = 4.4 Hz, 2H) 4.78 (q, J = 6.8 Hz, 1H) 6.68(dd, J = 8.3, 2.4 Hz, 1H) 6.76-6.78 (m, 1H) 6.89 (d, J = 8.3 Hz, 1H)7.22 (t, J = 7.8 Hz, 1H) 7.63 (br s, 1H).

TABLE 12 Ex- ample No. Structural formula Physicochemical data 4(4b)

1H NMR (CDCl) δ(ppm) 1.20-1.24 (m ,9H) 1.45 (s, 9H) 1.78 (d, J = 6.8 Hz,3H) 1.83-2.02 (m, 4H) 2.15- 2.18 (m, 2H) 2.51-2.54 (m, 1H) 2.81-2.85 (m,1H) 3.61 (s, 3H) 4.41 (br s, 1H) 5.72 (q, J = 6.7 Hz, 1H) 6.80-6.83 (m,3H) 7.16 (t, J = 8.1 Hz, 1H). 4(4c)

1H NMR (CDCl) δ(ppm) 1.20 (d, J = 6.8 Hz, 3H) 1.21 (d, J = 7.3 Hz, 3H)1.22 (m, 2H) 1.78 (d, J = 6.8 Hz, 3H) 1.80-1.86 (m, 1H) 1.92-2.00 (m,5H) 2.50-2.53 (m, 1H) 2.76-2.87 (m, 2H) 3.62 (s, 3H) 5.73 (q, J =6.7 Hz,1H) 6.79-6.84 (m, 3H) 7.16 (t, J = 8.1 Hz, 1H). 4(4d)

1H NMR (CDCl₃) δ(ppm) 1.20 (d, J = 6.7 Hz, 3H) 1.21 (d, J = 6.7 Hz, 3H)1.40-1.51 (m, 2H) 1.60-1.64 (m, 1H) 1.79 (d, J = 6.8 Hz, 3H) 1.81-1.88(m, 1H) 1.98- 2.06 (m, 2H) 2.14-2.20 (m, 2H) 2.57 (tt, J = 11.7, 3.5 Hz,1H) 2.82-2.85 (m, 1H) 3.41 (tt, J = 11.2, 4.1 Hz, 1H) 3.62 (s, 3H) 5.72(q, J = 6.7 Hz, 1H) 6.79-6.81 (m, 1H) 6.84-6.85 (m, 2H) 7.17 (t, J = 7.8Hz, 1H). 4(4e)

1H NMR (CDCl₃) δ(ppm) 1.19-1.23 (m, 6H) 1.47 (s, 9H) 1.58-1.61 (m, 2H)1.80 (d, J = 6.8 Hz, 3H) 1.89- 1.91 (m, 2H) 1.99-2.05 (m, 4H) 2.13-2.20(m, 2H) 2.39-2.41 (m, 2H) 2.48-2.54 (m, 1H) 2.71-2.73 (m, 1H) 2.84-2.86(m, 1H) 3.35-3.37 (m, 2H) 3.66 (s, 3H) 3.87 (br s, 2H) 4.50-4.52 (m, 1H)5.74 (q, J = 6.8 Hz, 1H) 6.81-6.85 (m, 3H) 7.18 (t, J = 8.3 Hz, 1H) 7.47(s, 1H). 4(4f)

1H NMR (CDCl₃) δ(ppm) 1.19-1.22 (m, 6H) 1.47 (s, 9H) 1.59-1.65 (m, 2H)1.80 (d, J = 6.8 Hz, 3H) 1.94- 2.29 (m, 8H) 2.36-2.46 (m, 2H) 2.69-2.76(m, 1H) 2.81-2.89 (m, 1H) 3.21-3.33 (m, 2H) 3.66 (s, 3H) 3.92-4.05 (m,2H) 4.49-4.56 (m, 1H) 5.75 (q, J = 6.7 Hz, 1H) 6.79-6.87 (m, 3H) 7.18(t, J = 8.3 Hz, 1H) 7.59 (s, 1H). 4(4g)

1H NMR (CDCl₃) δ(ppm) 1.21 (d, J = 6.8 Hz, 6H) 1.80 (d, J = 6.8 Hz, 3H)2.02-2.03 (m, 4H) 2.12-2.31 (m, 6H) 2.34 (s, 3H) 2.43-2.46 (m, 4H) 2.71(s, 3H) 2.82- 2.88 (m, 1H) 3.66 (s, 3H) 4.51 (s, 1H) 5.74 (q, J = 6.5Hz, 1H) 6.81-6.85 (m, 3H) 7.17-7.18 (m, 1H) 7.57 (s, 1H). MS (APCI) m/z:510 [M + H]⁺. 5(5a)

1H NMR (CDCl₃) δ(ppm) 1.09 (s, 9H) 3.90 (d, J = 4.4 Hz, 2H) 4.20 (s, 2H)7.38-7.43 (m, 4H) 7.45-7.47 (m, 2H) 7.60-7.61 (m, 4H) 7.88 (br s, 1H).

TABLE 13 Ex- ample No. Structural formula Physicochemical data 5(5b)

1H NMR (CDCl₃) δ(ppm) 1.05 (s, 9H) 1.20-1.27 (m, 2H) 1.46 (s, 9H)1.84-1.94 (m, 2H) 2.01-2.04 (m, 2H) 2.17-2.20 (m, 2H) 2.54-2.59 (m, 1H)3.53-3.55 (m, 1H) 3.59 (s, 3H) 4.43 (br s, 1H) 4.86 (s, 2H) 7.38- 7.40(m, 4H) 7.43-7.46 (m, 2H) 7.64-7.66 (m, 4H). 5(5c)

1H NMR (CDCl₃) δ(ppm) 1.06 (s, 9H) 1.43-1.52 (m, 2H) 1.83-1.88 (m, 2H)2.05-2.09 (m, 2H) 2.18-2.20 (m, 2H) 2.61 (tt, J = 11.7, 3.7 Hz, 1H) 3.42(tt, J = 11.2, 4.1 Hz, 1H) 3.61 (s, 3H) 4.87 (s, 2H) 7.39-7.40 (m, 4H)7.44-7.46 (m, 2H) 7.64-7.66 (m, 4H). 5(5d)

1H NMR (CDCl₃) δ(ppm) 1.06 (s, 9H) 1.96-2.27 (m, 11H) 2.39-2.47 (m, 2H)2.72-2.79 (m, 1H) 2.96-3.03 (m, 2H) 3.05-3.12 (m, 2H) 3.64 (s, 3H)4.49-4.56 (m, 1H) 4.88 (s, 2H) 7.38-7.48 (m, 6H) 7.58 (s, 1H) 7.65-7.68(m, 4H). 5(5e)

1H NMR (CDCl3) δ(ppm) 1.06 (s, 9H) 2.03-2.04 (m, 5H) 2.22-2.25 (m, 5H)2.33-2.35 (m, 1H) 2.35 (s, 3H) 2.38-2.49 (m, 3H) 2.74-2.76 (m, 3H) 3.64(s, 3H) 4.51-4.53 (m, 1H) 4.88 (s, 2H) 7.40-7.46 (m, 6H) 7.59 (s, 1H)7.66-7.66 (m, 4H). 5(5f)

1H NMR (CDCl₃) δ(ppm) 1.95-2.01 (m, 5H) 2.16- 2.21 (m, 5H) 2.25-2.31 (m,1H) 2.31 (s, 3H) 2.39- 2.44 (m, 4H) 2.71-2.74 (m, 3H) 3.70 (s, 3H) 4.49-4.52 (m, 1H) 4.76 (s, 2H) 7.56 (s, 1H). 5(5g)

1H NMR (CDCl₃) δ(ppm) 1.99-2.13 (m, 4H) 2.17- 2.34 (m, 6H) 2.35 (s, 3H)2.41-2.50 (m, 4H) 2.71- 2.84 (m, 3H) 3.71 (s, 3H) 4.49-4.58 (m, 1H) 5.30(s, 2H) 7.22 (dd, J = 8.8, 3.4 Hz, 1H) 7.33 (d, J = 3.4 Hz, 1H) 7.42 (d,J = 8.8 Hz, 1H) 7.59 (s, 1H). MS (APCI) m/z: 556 [M + H]⁺. 6(6a)

1H NMR (CDCl₃) δ(ppm) 1.20 (d, J = 6.3 Hz, 3H) 2.00-2.06 (m, 2H)3.05-3.11 (m, 2H) 3.14-3.20 (m, 2H) 3.28-3.34 (m, 1H) 3.90 (s, 3H) 7.38(d, J = 8.3 Hz, 2H) 7.97 (d, J = 8.3 Hz, 2H). 6(6b)

1H NMR (CDCl₃) δ(ppm) 1.19 (d, J = 6.3 Hz, 3H) 1.99-2.04 (m, 2H) 3.06(q, J = 7.0 Hz, 2H) 3.17 (q, J = 7.0 Hz, 2H) 3.25 (q, J = 6.3 Hz, 1H)4.67 (s, 2H) 7.29-7.33 (m, 4H).

TABLE 14 Ex- ample No. Structural formula Physicochemical data 6(6c)

1H NMR (CDCl) δ(ppm) 1.18 (d, J = 6.8 Hz, 3H) 1.99-2.04 (m, 2H)3.03-3.08 (m, 3H) 3.16 (q, J = 7.0 Hz, 2H) 3.24 (q, J = 6.5 Hz, 1H) 7.26(d, J = 8.3 Hz, 2H) 7.43 (d, J = 8.3 Hz, 2H). 6(6d)

1H NMR (CDCl₃) δ(ppm) 1.22 (d, J = 6.8 Hz, 3H) 1.24 (d, J = 7.3 Hz, 6H)2.02-2.10 (m, 6H) 2.23-2.24 (m, 2H) 2.46-2.48 (m, 2H) 2.80-2.82 (m, 1H)2.86- 2.92 (m, 1H) 3.09 (q, J = 7.0 Hz, 2H) 3.20 (q, J = 7.0 Hz, 2H)3.28 (q, J = 6.5 Hz, 1H) 3.70 (s, 3H) 4.58 (s, 1H) 5.27 (s, 2H)6.86-6.91 (m, 3H) 7.24 (t, J = 8.5 Hz, 1H) 7.37 (d, J = 7.8 Hz, 2H)7.77-7.78 (m, 3H). MS (APCI) m/z: 540 [M + H]⁺. 7(7a)

1H NMR (DMSO-d₆) δ(ppm) 1.36 (s, 9H) 1.64-1.75 (m, 12H) 2.71 (s, 3H)6.40 (br s, 1H) 7.31-7.33 (m, 1H). 7(7b)

1H NMR (DMSO-d₆) δ(ppm) 1.36 (s, 9H) 1.69-1.80 (m, 6H) 1.80-1.88 (m, 6H)2.94 (d, J = 4.8 Hz, 3H) 6.43 (br s, 1H) 9.25 (d, J = 4.0 Hz, 1H). 7(7c)

1H NMR: (CDCl₃) δ 1.23-1.25 (m, 6H) 1.63 (d, J = 6.8 Hz, 3H) 2.82-2.94(m, 1H) 3.77 (s, 3H) 4.80 (q, J = 6.8 Hz, 1H) 6.68-6.69 (m, 1H)6.80-6.82 (m, 1H) 6.86 (dd, J = 7.7, 0.6 Hz, 1H) 7.18-7.22 (m, 1H).7(7d)

1H NMR (CDCl₃) δ(ppm) 1.22-1.24 (m, 6H) 1.55- 1.59 (m, 3H) 2.84-2.91 (m,1H) 3.89 (br s, 2H) 4.74- 4.79 (m, 1H) 6.67-6.69 (m, 1H) 6.78 (s, 1H)6.87- 6.89 (m, 1H) 7.18-7.21 (m, 1H) 7.82-8.06 (m, 1H). 7(7e)

1H NMR (CDCl₃) δ(ppm) 1.14-1.17 (m, 9H) 1.74 (d, J = 6.8 Hz, 3H)1.92-2.01 (m, 2H) 2.21-2.34 (m, 12H) 2.77-2.84 (m, 1H) 3.02-3.26 (m, 5H)3.75 (s, 3H) 5.66 (q, J = 6.8 Hz, 1H) 6.74-6.80 (m, 3H) 7.12 (t, J = 8.0Hz, 1H) 7.30 (d, J = 8.0 Hz, 2H) 7.68-7.71 (m, 3H). MS (ESI) m/z: 580[M + H]⁺. 8(8a)

1H NMR (CDCl₃) δ(ppm) 1.23 (d, J = 6.9 Hz, 3H) 1.24 (d, J = 6.9 Hz, 3H)1.48 (s, 9H) 1.50-2.25 (m, 11H) 1.82 (d, J = 6.9 Hz, 3H) 2.38-2.45 (m,2H) 2.69-2.75 (m, 1H) 2.84-2.90 (m, 1H) 3.23 (t, J = 10.7 Hz, 1H) 3.68(s, 3H) 4.17-4.23 (m, 1H) 4.35-4.50 (m, 1H) 4.51-4.58 (m, 2H) 5.77 (q, J= 6.9 Hz, 1H) 6.83-6.88 (m, 3H) 7.18-7.22 (m, 1H) 7.55 (s, 1H).

TABLE 15 Ex- ample No. Structural formula Physicochemical data 8(8b)

1H NMR (DMSO-d₆) δ(ppm) 1.16 (d, J = 6.8 Hz, 3H) 1.17 (d, J = 6.8 Hz,3H) 1.31-2.40 (m, 14H) 1.67 (d, J = 6.5 Hz, 3H) 2.50 (s, 6H) 2.80-2.93(m, 2H) 3.58 (s, 3H) 4.00-4.03 (m, 1H) 4.38 (dd, J = 11.5, 2.0 Hz, 1H)4.54-4.69 (m, 1H) 5.76 (q, J = 6.5 Hz, 1H) 6.84-6.87 (m, 3H) 7.20 (t, J= 7.9 Hz, 1H) 8.04 (s, 1H). MS (APCI) m/z: 522 [M + H]⁺. 9(9a)

1H NMR (CDCl₃) δ(ppm) 1.42 (s, 9H) 1.79-1.89 (m, 2H) 1.94-2.04 (m, 2H)2.07-2.17 (m, 2H) 2.26-2.36 (m, 2H) 2.45 (s, 1H) 4.00 (s, 2H) 4.28 (brs, 1H). 9(9b)

1H NMR (CDCl₃) δ(ppm) 1.20-1.33 (m, 2H) 1.45 (s, 9H) 1.83-1.95 (m, 2H)1.99-2.07 (m, 2H) 2.20 (br d, J = 12.2 Hz, 2H) 2.60 (tt, J = 12.1, 3.5Hz, 1H) 3.48- 3.60 (m, 1H) 3.66 (s, 3H) 4.43 (br s, 1H) 5.28 (s, 2H)7.22-7.31 (m, 3H) 7.42 (t, J = 7.9 Hz, 1H). 9(9c)

1H NMR (CDCl₃) δ(ppm) 1.18-1.29 (m, 2H) 1.79- 1.91 (m, 2H) 1.96-2.07 (m,4H) 2.54-2.65 (m, 1H) 2.76-2.86 (m, 1H) 3.66 (s, 3H) 5.28 (s, 2H) 7.22-7.29 (m, 3H) 7.39-7.43 (m, 1H). 9(9d)

1H NMR (CDCl₃) δ(ppm) 1.48-1.58 (m, 2H) 1.80- 1.89 (m, 2H) 2.09-2.13 (m,2H) 2.19-2.23 (m, 2H) 2.60-2.76 (m, 1H) 3.41-3.48 (m, 1H) 3.69 (s, 3H)5.30 (s, 2H) 7.25-7.30 (m, 3H) 7.41-7.49 (m, 1H). 9(9e)

1H NMR (CDCl₃) δ(ppm) 1.44 (s, 9H) 1.88-2.10 (m, 6H) 2.16-2.32 (m, 8H)2.35-2.44 (m, 2H) 2.72-2.81 (m, 1H) 3.69 (s, 3H) 4.12 (s, 2H) 4.33-4.38(m, 1H) 4.46-4.55 (m, 1H) 5.31 (s, 2H) 7.24-7.31 (m, 3H) 7.43 (t, J =7.6 Hz, 1H) 7.50 (s, 1H). 9(9f)

1H NMR (CDCl₃) δ(ppm) 1.77-2.10 (m, 8H) 2.14- 2.29 (m, 6H) 2.26 (s, 6H)2.36-2.44 (m, 2H) 2.72- 2.81 (m, 1H) 3.70 (s, 3H) 3.94 (s, 2H) 4.48-4.56(m, 1H) 5.31 (s, 2H) 7.23-7.31 (m, 3H) 7.43 (t, J = 7.9 Hz, 1H) 7.50 (s,1H). MS (APCI) m/z: 560 [M + H]⁺. 10(10a)

1H NMR (CDCl₃) δ(ppm) 1.81 (s, 12H) 2.21-2.29 (m, 2H) 3.65 (s, 3H) 4.00(br s, 2H) 4.36 (br s, 2H).

TABLE 16 Ex- ample No. Structural formula Physicochemical data 10(10b)

1H NMR (CDCl₃) δ(ppm) 1.40 (s, 12H) 2.06-2.19 (m, 2H) 2.16 (s, 2H)3.22-3.26 (m, 5H). 10(10c)

1H NMR (CDCl₃) δ(ppm) 1.42-1.46 (m, 6H) 1.60- 1.64 (m, 6H) 2.07-2.10 (m,2H) 2.17 (s, 2H) 3.23 (t, J = 6.8 Hz, 2H) 9.44 (s, 1H). 10(10d)

1H NMR (CDCl₃) δ(ppm) 1.29-1.33 (m, 6H) 1.65- 1.69 (m, 6H) 1.99-2.01 (m,3H) 2.05 (s, 2H) 3.15 (t, J = 7.2 Hz, 2H). 10(10e)

1H NMR (CDCl₃) δ(ppm) 1.49-1.53 (m, 6H) 1.84- 1.88 (m, 6H) 2.03-2.10 (m,6H) 2.19 (br s, 4H) 2.41 (br s, 2H) 2.80 (br s, 1H) 3.24 (t, J = 6.8 Hz,4H) 3.71 (s, 3H) 4.47-4.51 (m, 1H) 5.32 (s, 2H) 7.23-7.30 (m, 4H) 7.45(t, J = 7.6 Hz, 1H). MS (ESI) m/z: 584 [M + H]⁺. 11

1H NMR (CDCl₃) δ(ppm) 1.72-1.81 (m, 6H) 1.93- 2.00 (m, 6H) 2.01-2.11 (m,4H) 2.22 (d, J = 7.8 Hz, 2H) 2.32 (s, 6H) 2.42 (d, J = 7.2 Hz, 2H)2.76-2.83 (m, 1H) 3.72 (s, 3H) 4.44-4.54 (m, 1H) 5.32 (s, 2H) 7.25-7.28(m, 3H) 7.30 (s, 1H) 7.42-7.48 (m, 1H). MS (ESI) m/z: 558 [M + H]⁺. 12

1H NMR (CDCl₃) δ(ppm) 1.88-2.00 (m, 4H) 2.05 (s, 6H) 2.09-2.17 (m, 2H)2.22 (s, 6H) 2.28-2.39 (m, 2H) 2.63-2.81 (m, 1H) 3.63 (s, 3H) 4.37-4.48(m, 1H) 5.24 (s, 2H) 7.16-7.23 (m, 4H) 7.32-7.40 (m, 1H). MS (ESI) m/z:516 [M + H]⁺. 13(13a)

1H NMR (CDCl₃) δ(ppm) 1.32-1.50 (m, 11H) 2.08- 2.18 (m, 1H) 2.55-2.65(m, 1H) 3.07 (t, J = 10.6 Hz, 1H) 3.18 (d, J = 4.9 Hz, 3H) 3.46-3.73 (m,1H) 4.02-4.14 (m, 1H) 4.15-4.33 (m, 2H) 8.42 (br s, 1H). 13(13b)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.8 Hz, 6H) 1.43-1.49 (m, 9H)1.52-1.62 (m, 1H) 2.22 (br s, 2H) 2.24-2.37 (m, 1H) 2.84-2.94 (m, 1H)3.24 (t, J = 10.3 Hz, 1H) 3.73 (br s, 1H) 3.76 (s, 3H) 4.08-4.14 (m, 1H)4.32-4.53 (m, 1H) 4.53-4.72 (m, 1H) 5.19-5.30 (m, 2H) 6.84-6.91 (m, 3H)7.28-7.38 (m, 1H).

TABLE 17 Ex- ample No. Structural formula Physicochemical data 13(13c)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.8, 6H) 1.48- 1.56 (m, 1H) 2.18-2.32(m, 3H) 2.45-2.67 (m, 2H) 2.85-2.93 (m, 1H) 3.02-3.08 (m, 1H) 3.28-3.33(m, 1H) 3.75 (s, 3H) 4.04-4.08 (m, 1H) 4.52-4.56 (m, 1H) 5.20-5.27 (m,2H) 6.83-6.90 (m, 3H) 7.22 (t, J = 7.8 Hz, 1H). 13(13d)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.7 Hz, 6H) 1.68-1.77 (m, 1H)2.28-2.36 (m, 2H) 2.40-2.48 (m, 1H) 2.84-2.93 (m, 1H) 3.41 (dd, J =11.2, 9.4 Hz, 1H) 3.54-3.62 (m, 1H) 3.75 (s, 3H) 3.99-4.04 (m, 1H)4.56-4.61 (m, 1H) 5.25 (dd, J = 17.9, 12.5 Hz, 2H) 6.83-6.91 (m, 3H)7.23 (t, J = 7.9 Hz, 1H). 13(13e)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.7 Hz, 6H) 1.48 (s, 9H) 2.08-2.17(m, 3H) 2.19-2.53 (m, 4H) 2.61-2.69 (m, 1H) 2.84-2.93 (m, 1H) 3.21-3.31(m, 2H) 3.79 (s, 3H) 3.91-4.10 (m, 3H) 4.29-4.34 (m, 1H) 4.63-4.77 (m,2H) 5.28 (dd, J = 17.9, 12.5 Hz, 2H) 6.84-6.91 (m, 2H) 7.19-7.25 (m, 1H)7.32-73.8 (m, 1H) 7.64-7.69 (m, 1H). 13(13f)

1H NMR (CDCl₃) δ(ppm) 1.24 (d, J = 6.7 Hz, 6H) 2.05-2.53 (m, 9H) 2.35(s, 3H) 2.60-2.68 (m, 1H) 2.70-2.78 (m, 2H) 2.84-2.93 (m, 1H) 3.79 (s,3H) 3.94-4.01 (m, 1H) 4.29-4.34 (m, 1H) 4.63-4.77 (m, 2H) 5.27 (dd, J =17.9, 12.5 Hz, 2H) 6.84-6.91 (m, 3H) 7.23 (t, J = 8.2 Hz, 1H) 7.68 (s,1H). MS (APCI) m/z: 498 [M + H]⁺. 14(14a)

1H NMR (CDCl₃) δ(ppm) 1.26 (d, J = 6.8 Hz, 6H) 2.89-2.91 (m, 1H)2.95-3.01 (m, 1H) 3.07-3.12 (m, 1H) 3.35-3.39 (m, 2H) 3.65-3.73 (m, 1H)3.82 (s, 3H) 3.93-3.97 (m, 1H) 4.45-4.60 (m, 3H) 6.83 (d, J = 8.4 Hz,2H) 7.03 (d, J = 8.8 Hz, 2H) 7.15-7.24 (m, 4H). 14(14b)

1H NMR (CDCl₃) δ(ppm) 1.17 (d, J = 6.8 Hz, 6H) 2.82-2.96 (m, 2H)3.07-3.15 (m, 1H) 3.24-3.29 (m, 1H) 3.35-3.50 (m, 1H) 3.60-3.66 (m, 1H)3.86-3.90 (m, 1H) 4.02-4.09 (m, 1H) 4.30 (d, J = 6.0 Hz, 1H) 7.04-7.19(m, 4H). 14(14c)

1H NMR (CDCl₃) δ(ppm) 1.27 (d, J = 6.8 Hz, 6H) 22.90-.92 (m, 1H)3.11-3.17 (m, 1H) 3.31-3.46 (m, 2H) 3.76-3.80 (m, 2H) 4.04-4.06 (m, 1H)4.69 (dd, J = 8.8, 2.8 Hz, 1H) 7.12-7.29 (m, 4H) 8.83-8.95 (m, 1H).

TABLE 18 Ex - ample No. Structural formula Physicochemical data 14(14d)

1H NMR (CDCl₃) δ(ppm) 1.32-1.39 (m, 2H) 1.45- 1.54 (m, 2H) 2.02-2.06 (m,4H) 2.24-2.30 (m, 1H) 3.25-3.31 (m, 1H) 3.65 (s, 3H). 14(14e)

1H NMR (CDCl₃) δ(ppm) 1.47 (s, 9H) 1.66-1.69 (m, 2H) 1.83-2.00 (m, 6H)2.22 (d, J = 12.8 Hz, 2H) 2.32 (d, J = 11.2 Hz, 2H) 2.30-2.42 (m, 1H)3.00-3.19 (m, 1H) 3.26-3.45 (m, 2H) 3.71 (s, 3H) 3.77-4.00 (m, 2H)4.36-4.52 (m, 1H) 7.40-7.55 (br s, 1H). 14(14f)

1H NMR (CDCl₃) δ(ppm) 1.40 (s, 9H) 1.59-1.62 (m, 2H) 1.76-1.80 (m, 2H)2.04-2.07 (m, 3H) 2.13-2.16 (m, 3H) 2.24-2.38 (m, 3H) 3.10-3.26 (br s,2H) 3.64 (s, 3H) 3.80-4.06 (br s, 2H) 4.35-4.42 (m, 1H), 7.49 (s, 1H).14(14g)

1H NMR (DMSO-d₆) δ(ppm) 1.41 (s, 9H) 1.61-1.64 (m, 2H) 1.77-1.85 (m, 4H)1.91 (s, 2H) 1.97-2.22 (m, 7H) 3.64-3.68 (m, 2H) 4.47-4.53 (m, 1H) 8.39(s, 1H) 9.04 (s, 1H). 14(14h)

1H NMR (CDCl₃) δ(ppm) 1.18 (d, J = 6.8 Hz, 6H) 1.89-2.05 (m, 4H)2.08-2.20 (m, 5H) 2.32 (s, 3H) 2.34-2.45 (m, 2H) 2.71-2.85 (m, 5H)3.00-3.07 (m, 3H) 3.55-3.58 (m, 1H) 3.74-3.86 (m, 3H) 4.17-4.19 (m, 1H)4.46-4.51 (m, 1H) 4.97-4.99 (dd, J = 9.6, 6.4 Hz, 1H) 7.04-7.19 (m, 4H)7.52 (s, 1H). MS (ESI) m/z: 522 [M + H]⁺. 15(15a)

1H NMR (CDCl₃) δ(ppm) 1.70-1.96 (m, 2H) 2.10- 2.14 (m, 1H) 2.18-2.28 (m,1H) 3.31-3.50 (m, 2H) 4.75 (dd, J = 7.6, 5.6 Hz, 1H) 6.33 (s, 1H)7.22-7.29 (m, 2H) 7.37-7.44 (m, 1H) 7.55-7.59 (m, 1H). 15(15b)

1H NMR (CDCl₃) δ(ppm) 1.84-1.97 (m, 1H) 2.07- 2.24 (m, 3H) 3.33-3.58 (m,2H) 5.06 (t, J = 4.4 Hz, 1H) 7.25-7.29 (m, 1H,) 7.32-7.38 (m, 2H) 7.39-7.47 (m, 1H) 8.75-9.10 (m, 1H). 15(15c)

1H NMR (CDCl₃) δ(ppm) 1.47-1.51 (m, 9H) 1.99- 2.28 (m, 12H) 2.41-2.56(m, 4H) 2.75-2.88 (m, 1H) 3.12-3.41 (m, 3H) 3.85 (d, J = 11.7, 5.1 Hz,1H) 4.01 (s, 2H) 4.13-4.24 (m, 1H) 5.64-5.74 (m, 1H) 7.27 (d, J = 7.7Hz, 1H) 7.39-7.48 (m, 2H) 7.50-7.55 (m, 1H) 7.62 (s, 1H).

TABLE 19 Example No. Structural formula Physicochemical data 15(15d)

1H NMR (CDCl₃) δ (ppm) 1.88-2.22 (m, 12H) 2.28 (s, 3H) 2.32-2.45 (m, 6H)2.60-2.79 (m, 3H) 3.72- 3.79 (m, 1H) 4.06-4.10 (m, 1H) 4.45 (s, 1H)5.56- 5.63 (m, 1H) 7.16-7.18 (m, 1H) 7.30-7.39 (m, 2H) 7.42-7.47 (m, 1H)7.51 (s, 1H). MS (ESI) m/z: 548 [M + H]⁺. 16(16a)

1H NMR (CDCl₃) δ (ppm) 3.35 (d, J = 4.6 Hz, 3H) 7.48 (d, J = 8.4 Hz, 2H)7.62 (m, 1H) 7.73 (d, J = 8.4 Hz, 2H). 16(16b)

1H NMR (CDCl₃) δ (ppm) 3.78 (s, 3H) 5.38 (s, 2H) 7.28-7.31 (m, 3H)7.39-7.47 (m, 3H) 7.88 (d, J = 8.4 Hz, 2H). 16(16c)

1H NMR (CDCl₃) δ (ppm) 3.82 (s, 3H) 5.40 (s, 2H) 7.29-7.32 (m, 3H)7.44-7.47 (m, 1H) 7.72 (s, 1H) 7.79 (d, J = 9.2 Hz, 2H) 7.84 (d, J = 9.2Hz, 2H) 8.03 (s, 1H). 16(16d)

1H NMR (CDCl₃) δ (ppm) 2.51 (s, 3H) 2.59-2.64 (m, 2H) 2.79-2.84 (m, 2H)3.22-3.27 (m, 2H) 3.82 (s, 3H) 5.40 (s, 2H) 6.03-6.06 (m, 1H) 7.28-7.32(m, 3H) 7.44-7.48 (m, 1H) 7.77 (d, J = 9.2 Hz, 2H) 7.83 (s, 1H) 7.86 (d,J = 9.2 Hz, 2H) 7.93 (s, 1H). 16(16e)

1H NMR (CDCl₃) δ (ppm) 1.71-1.79 (m, 2H) 1.98 (d, J = 13.8 Hz, 2H) 2.08(t, J = 11.5 Hz, 2H) 2.33 (s, 3H) 2.53-2.59 (m, 1H) 2.73 (d, J = 11.5Hz, 2H) 3.81 (s, 3H) 5.39 (s, 2H) 7.28-7.32 (m, 3H) 7.43-7.47 (m, 1H)7.64 (s, 1H) 7.74-7.79 (m, 3H) 7.84 (d, J = 9.2 Hz, 2H). MS (ESI) m/z:497 [M + H]⁺. 17(17a)

1H NMR (CDCl₃) δ (ppm) 1.60-1.78 (m, 2H) 2.06- 2.20 (m, 4H) 2.24-2.37(m, 1H) 3.55-3.72 (m, 3H) 4.05-4.14 (m, 1H) 7.30-7.43 (m, 2H). 17(17b)

1H NMR (DMSO-d₆) δ (ppm) 1.48-1.74 (m, 4H) 1.78 (d, J = 11.2 Hz, 2H)1.95-2.17 (m, 3H) 4.02-4.25 (m, 3H) 7.51 (s, 1H) 8.00 (1H, s, 1H) 9.01(s, 1H). 17(17c)

1H NMR (CDCl₃) δ (ppm) 3.30 (d, J = 4.8 Hz, 3H) 4.82-5.06 (m, 2H)7.08-7.12 (m, 1H) 7.20 (s, 1H) 7.26-7.33 (m, 1H) 7.41-7.48 (m, 1H)8.17-8.69 (m, 1H).

TABLE 20 Example No. Structural formula Physicochemical data 17(17d)

1H NMR (CDCl₃) δ (ppm) 2.66 (s, 3H) 3.16 (s, 3H) 4.79 (s, 2H), 7.10 (s,1H) 7.15-7.20 (m, 2H) 7.31- 7.34 (m, 1H). 17(17e)

1H NMR (CDCl₃) δ (ppm) 1.88-2.05 (m, 4H) 2.11- 2.27 (m, 3H) 2.29-2.38(m, 2H) 2.70-2.82 (m, 1H) 3.70 (s, 3H) 4.17-4.30 (m, 1H) 5.31 (s, 1H)5.28- 5.33 (m, 1H) 7.22-7.33 (m, 4H) 7.40-7.47 (m, 1H) 7.49 (d, J = 4.0Hz, 2H). 17(17f)

1H NMR (CDCl₃) δ (ppm) 1.47 (s, 9H) 1.68-1.76 (m, 1H) 1.95-2.08 (m, 6H)2.15-2.23 (m, 2H) 2.28-2.46 (m, 4H) 2.48-2.58 (m, 1H) 2.71-2.82 (m, 1H)3.70 (s, 3H) 3.81-3.92 (m, 1H) 4.16-4.26 (m, 1H) 4.56- 4.65 (m, 1H) 5.32(s, 2H) 5.91 (s, 1H) 7.24-7.32 (m, 3H) 7.40-7.46 (m, 2H) 7.59 (s, 1H).17(17g)

1H NMR (CDCl₃) δ (ppm) 1.18-1.28 (m, 2H) 1.38- 1.47 (m, 11H) 1.93-2.21(m, 10H) 2.28-2.36 (m, 2H) 2.41-2.48 (m, 1H) 2.71-2.81 (m, 1H) 3.40-3.54(m, 1H) 3.70 (s, 3H) 4.14-4.23 (m, 1H) 4.38-4.48 (m, 1H) 5.31 (s, 2H)7.23-7.29 (m, 4H) 7.37 (s, 1H) 7.44 (t, J = 7.6 Hz, 1H). 17(17h)

1H NMR (CDCl₃) δ (ppm) 1.05-1.15 (m, 2H) 1.27- 1.37 (m, 2H) 1.83-1.91(m, 2H) 1.94-2.03 (m, 7H) 2.05-2.10 (m, 2H) 2.15-2.22 (m, 2H) 2.29-2.36(m, 2H) 2.40-2.48 (m, 1H) 2.71-2.81 (m, 1H) 3.22 (t, J = 7.2 Hz, 4H)3.70 (s, 3H) 4.13-4.22 (m, 1H) 5.31 (s, 2H) 7.23 (s, 1H) 7.26-7.29 (m,3H) 7.38 (s, 1H) 7.44 (t, J = 8.0 Hz, 1H). MS (ESI) m/z: 543 [M + H]⁺.18(18a)

1H NMR (CDCl₃) δ (ppm) 2.41 (s, 3H) 2.44-2.49 (m, 2H) 2.65 (t, J = 5.7Hz, 2H) 2.86 (s, 6H) 3.12-3.15 (m, 2H) 6.50 (s, 1H) 7.07 (s, 1H)7.83-7.85 (m, 1H). 18(18b)

1H NMR (DMSO-d₆) δ (ppm) 2.56-2.68 (m, 1H) 2.80 (s, 3H) 3.12-3.25 (m,1H) 3.29-3.60 (m, 2H) 3.67- 3.82 (m, 1H) 3.89-4.01 (m, 1H) 6.52 (s, 1H)7.81 (s, 1H) 9.16 (s, 1H) 11.08 (br s, 1H). 18(18c)

1H NMR (CD₃OD) δ (ppm) 1.94-2.05 (m, 2H) 2.25- 2.35 (m, 2H) 2.91 (s, 3H)3.10-3.24 (m, 4H) 3.61- 3.66 (m, 2H) 7.46 (s, 1H) 8.90 (s, 1H). 18(18d)

1H NMR (CDCl₃) δ (ppm) 1.68-1.80 (m, 2H) 2.04- 2.15 (m, 4H) 2.32 (s, 3H)2.58-2.67 (m, 1H) 2.93- 2.98 (m, 2H) 3.83 (s, 3H) 5.40 (s, 2H) 7.06 (s,1H) 7.28-7.34 (m, 3H) 7.46 (t, J = 8.0 Hz, 1H) 7.52-7.58 (m, 2H) 7.79(s, 1H) 7.80 (s, 1H) 7.87 (s, 1H). MS (APCI) m/z: 497 [M + H]⁺.

TABLE 21 Example No. Structural formula Physicochemical data 19(19a)

1H NMR (CDCl₃) δ (ppm) 1.38-1.58 (m, 4H) 1.92- 1.98 (m, 2H) 2.01-2.09(m, 3H) 2.27-2.34 (m, 1H) 2.81 (d, J = 4.9 Hz, 3H) 3.67 (s, 3H)5.40-5.48 (m, 1H). 19(19b)

1H NMR (CDCl₃) δ (ppm) 1.44-1.54 (m, 2H) 1.69- 1.79 (m, 2H) 1.93-1.98(m, 2H) 2.07-2.12 (m, 2H) 2.31-2.38 (m, 1H) 2.41-2.48 (m, 1H) 3.19 (d, J= 4.9 Hz, 3H) 3.67 (s, 3H) 7.26-7.31 (m, 1H). 19(19c)

1H NMR (CDCl₃) δ (ppm) 1.44-1.56 (m, 4H) 1.79- 1.85 (m, 0.7H) 1.88-1.97(m, 1.3H) 2.04-2.11 (m, 2H) 2.20 (s, 1H) 2.29-2.36 (m, 1H) 2.42 (s, 2H)2.47-2.53 (m, 0.7H) 2.80-2.87 (m, 0.3H) 3.17 (s, 2H) 3.26 (s, 1H) 3.67(s, 1.3H) 3.67 (s, 0.7H). 19(19d)

1H NMR (CDCl₃) δ: 1.52-1.64 (m, 2H) 1.87-1.98 (m, 2H) 2.06-2.14 (m, 2H)2.16-2.23 (m, 2H) 2.47 (dt, J = 12.2, 3.4 Hz, 1H) 2.75 (dt, J = 12.2,3.4 Hz, 1H) 3.70 (s, 3H) 3.78 (s, 3H) 5.40 (s, 2H) 7.22-7.32 (m, 3H)7.45 (t, J = 7.8 Hz, 1H). 19(19e)

1H NMR (CDCl₃) δ: 1.08-1.20 (m, 2H) 1.34 (d, J = 5.4 Hz, 1H) 1.55-1.72(m, 1H) 1.76-1.89 (m, 2H) 1.94-2.11 (m, 4H) 2.62 (dt, J = 12.2, 3.4 Hz,1H) 3.53 (t, J = 5.9 Hz, 2H) 3.66 (s, 3H) 5.29 (s, 2H) 7.22-7.29 (m, 3H)7.42 (t, J = 7.8 Hz, 1H). 19(19f)

¹H-NMR (CDCl₃) δ: 1.36-1.47 (m, 2H) 1.82-1.92 (m, 2H) 2.09-2.16 (m, 2H)2.18-2.25 (m, 2H) 2.36- 2.44 (m, 1H) 2.64 (dt, J = 12.2, 3.4 Hz, 1H)3.67 (s, 3H) 5.30 (s, 2H) 7.22-7.31 (m, 3H) 7.43 (t, J = 7.8 Hz, 1H)9.70 (s, 1H). 19(19g)

1H NMR (CDCl₃) δ (ppm) 1.43-2.20 (m, 8H) 2.11 (s, 1H) 2.40-2.45 (m, 1H)2.65-2.70 (m, 1H) 3.80 (s, 3H) 5.31 (s, 2H) 7.26-7.36 (m, 3H) 7.43-7.46(m, 1H). 19(19h)

1H NMR (CDCl₃) δ (ppm) 0.06 (s, 6H) 0.89 (s, 9H) 1.35-1.55 (m, 2H)1.78-1.85 (m, 1H) 2.16-2.22 (m, 1H) 3.17 (t, J = 10.7 Hz, 1H) 3.28-3.33(m, 1H) 3.37- 3.45 (m, 1H) 3.51 (dd, J = 10.7, 5.4 Hz, 1H) 3.65 (dd, J =10.7, 5.9 Hz, 1H) 4.00-4.04 (m, 1H). 19(19i)

1H NMR (CDCl₃) δ (ppm) 0.08 (s, 6H) 0.91 (s, 9H) 1.53-2.40 (m, 12H)2.69-2.78 (m, 1H) 2.83-2.91 (m, 1H) 3.47-3.51 (m, 1H) 3.57-3.61 (m, 1H)3.64- 3.69 (m, 1H) 3.68 (s, 3H) 3.72-3.75 (m, 1H) 4.25- 4.28 (m, 1H)4.50-4.56 (m, 1H) 5.30 (s, 2H) 7.24- 7.28 (m, 4H) 7.41-7.44 (m, 1H).

TABLE 22 Example No. Structural formula Physicochemical data 19(19j)

1H NMR (CDCl₃) δ (ppm) 1.61-2.36 (m, 12H) 2.40- 2.44 (m, 1H) 2.72-2.78(m, 1H) 2.87-2.93 (m, 1H) 3.60-3.77 (m, 4H) 3.71 (s, 3H) 4.32-4.38 (m,1H) 4.54-4.61 (m, 1H) 5.32 (s, 2H) 7.27-7.32 (m, 4H) 7.42-7.47 (m, 1H).19(19k)

1H NMR (CDCl₃) δ (ppm) 1.48-2.15 (m, 11H) 2.23- 2.27 (m, 2H) 2.34-2.39(m, 1H) 2.45 (dd, J = 8.5, 4.0 Hz, 1H) 2.60 (dd, J = 7.4, 5.1 Hz, 1H)2.69-2.75 (m, 1H) 2.84-2.89 (m, 1H) 3.22-3.29 (m, 4H) 3.38-3.42 (m, 1H)3.61-3.67 (m, 1H) 3.67 (s, 3H) 4.24-4.27 (m, 1H) 4.48-4.54 (m, 1H) 5.30(s, 2H) 7.24-7.27 (m, 4H) 7.42 (t, J = 7.9 Hz, 1H). MS (APCI) m/z: 560[M + H]⁺. 20(20a)

1H NMR (CDCl₃) δ (ppm) 1.05 (s, 9H) 1.52-1.64 (m, 2H) 1.76-1.87 (m, 2H)2.01-2.11 (m, 2H) 2.12-2.22 (m, 2H) 2.39-2.47 (m, 1H) 2.57-2.65 (m, 1H)3.60 (s, 3H) 3.70 (s, 3H) 4.87 (s, 2H) 7.36-7.48 (m, 6H) 7.62-7.68 (m,4H). 20(20b)

1H NMR (CDCl₃) δ (ppm) 1.03 (s, 9H) 1.08-1.14 (m, 1H) 1.56-1.65 (m, 1H)1.72-1.87 (m, 3H) 1.92-2.02 (m, 5H) 2.51-2.59 (m, 1H) 3.47-3.51 (m, 2H)3.57 (s, 3H) 4.84 (s, 2H) 7.35-7.39 (m, 4H) 7.40-7.44 (m, 2H) 7.62-7.65(m, 4H). 20(20c)

1H NMR (CDCl₃) δ (ppm) 1.03 (s, 9H) 1.32-1.42 (m, 2H) 1.73-1.87 (m, 2H)2.04-2.11 (m, 2H) 2.14-2.20 (m, 2H) 2.33-2.39 (m, 1H) 2.53-2.60 (m, 1H)3.58 (s, 3H) 4.84 (s, 2H) 7.34-7.45 (m, 6H) 7.62-7.66 (m, 4H) 9.67 (s,1H). 20(20d)

1H NMR (CDCl₃) δ (ppm) 1.06 (s, 9H) 1.47-1.58 (m, 2H) 1.73-1.83 (m, 2H)1.96-2.04 (m, 2H) 2.09 (d, J = 2.1 Hz, 1H) 2.14-2.22 (m, 2H) 2.34-2.44(m, 1H) 2.57-2.65 (m, 1H) 3.60 (s, 3H) 4.86 (s, 2H) 7.37- 7.48 (m, 6H)7.62-7.68 (m, 4H). 20(20e)

1H NMR (CDCl₃) δ (ppm) 1.47-1.58 (m, 2H) 1.68- 1.79 (m, 2H) 1.94-2.03(m, 2H) 2.09 (d, J = 2.0 Hz, 1H) 2.13-2.21 (m, 2H) 2.33-2.42 (m, 1H)2.58-2.66 (m, 1H) 3.64 (s, 3H) 3.81 (br s, 1H) 4.77 (s, 2H). 20(20f)

1H NMR (CDCl₃) δ (ppm) 1.48-1.60 (m, 2H) 1.75- 1.88 (m, 2H) 1.98-2.06(m, 2H) 2.09 (d, J = 2.4 Hz, 1H) 2.15-2.25 (m, 2H) 2.36-2.45 (m, 1H)2.62-2.71 (m, 1H) 3.64 (s, 3H) 5.58 (s, 2H) 7.07 (s, 1H) 7.16 (d, J =5.4 Hz, 1H) 8.36 (d, J = 5.4 Hz, 1H). 20(20g)

1H NMR (CDCl₃) δ (ppm) 1.01-1.15 (m, 4H) 1.44 (s, 9H) 1.72-1.84 (m, 2H)1.88-2.07 (m, 3H) 2.70-2.86 (m, 1H) 2.98 (t, J = 6.8 Hz, 2H) 3.30-3.46(m, 3H) 4.35 (br s, 1H) 4.48 (dd, J = 7.4, 5.4 Hz, 2H).

TABLE 23 Ex- ample No. Structural formula Physicochemical data 20(20h)

1H NMR (CD₃OD) δ (ppm) 1.27-1.59 (m, 4H) 2.10- 2.24 (m, 4H) 3.05-3.23(m, 2H) 4.04-4.20 (m, 2H) 4.20-4.81 (m, 5H). 20(20i)

1H NMR (CDCl₃) δ (ppm) 1.16-1.29 (m, 2H) 1.60- 1.72 (m, 2H) 1.75-1.87(m, 2H) 1.90-2.04 (m, 4H) 2.06-2.18 (m, 4H) 2.20-2.33 (m, 4H) 2.69-2.93(m, 3H) 3.06 (d, J = 7.3 Hz, 1H) 3.41 (t, J = 6.8 Hz, 2H) 3.66 (s, 3H)4.34-4.44 (m, 1H) 4.45 (d, J = 5.4 Hz, 1H) 4.55 (d, J = 5.9 Hz, 1H) 5.59(s, 2H) 7.02 (s, 1H) 7.16 (d, J = 4.9 Hz, 1H) 7.28 (s, 1H) 8.36 (d, J =5.4 Hz, 1H). MS (APCI) m/z: 577 [M + H]⁺. 21(21a)

1H NMR (CDCl₃) δ (ppm) 1.23-1.28 (m, 3H) 1.56- 1.82 (m, 4H) 2.02-2.12(m, 2H) 2.18-2.29 (m, 2H) 2.32-2.45 (m, 4H) 2.51-2.64 (m, 1H) 3.68-3.70(m, 2H) 4.03-4.18 (m, 2H) 5.32-5.34 (m, 1H) 5.96-5.99 (m, 1H) 7.53 (s,1H) 7.60 (s, 1H). 21(2b)

1H NMR (CDCl₃) δ (ppm) 1.25-1.46 (m, 2H) 1.52- 1.77 (m, 6H) 1.87-1.98(m, 2H) 2.03-2.15 (m, 7H) 2.42-2.53 (m, 1H) 3.60-3.78 (m, 1H) 4.06-4.10(m, 1H) 5.33 (dd, J = 9.6, 2.4 Hz, 1H) 7.10 (s, 1H) 7.39- 7.41 (m, 2H).21(21c)

1H NMR (DMSO-d₆) δ (ppm) 1.35-1.55 (m, 2H) 1.60-1.77 (m, 2H) 1.91-2.10(m, 4H) 2.54-2.57 (m, 1H) 2.79-2.92 (m, 1H) 3.64 (s, 3H) 5.37 (s, 2H)7.36 (d, J = 7.6 Hz, 1H) 7.42 (d, J = 8.0 Hz, 1H) 7.46 (s, 3H) 7.54-7.60(m, 1H). 21(21d)

1H NMR (CDCl₃) δ (ppm) 1.05-1.13 (m, 2H) 1.38- 1.45 (m, 2H) 1.68-1.84(m, 2H) 1.84-1.87 (m, 4H) 1.97-2.10 (m, 9H) 2.52-2.70 (m, 2H) 3.14 (t, J= 7.2 Hz, 4H) 3.60 (s, 3H) 3.96-4.10 (m, 1H) 5.22 (s, 2H) 7.15-7.20 (m,4H) 7.30-7.37 (m, 2H). MS (ESI) m/z: 543 [M + H]⁺.

TABLE 24 Example No. Structural formula Physicochemical data 22(22a)

1H NMR (CDCl₃) δ (ppm) 1.05 (s, 9H) 1.19-1.30 (m, 1H) 1.36-1.50 (m, 10H)1.77-1.84 (m, 1H) 2.06- 2.15 (m, 1H) 2.97 (t, J = 10.7 Hz, 1H) 3.30-3.37(m, 1H) 3.51-3.67 (m, 2H) 3.71 (dd, J = 10.7, 4.9 Hz, 1H) 4.05 (ddd, J =10.7, 4.9, 2.0 Hz, 1H) 4.23 (br s, 1H) 7.33-7.45 (m, 6H) 7.63-7.69 (m,4H). 22(22b)

1H NMR (CDCl₃) δ (ppm) 1.05 (s, 9H) 1.15-1.28 (m, 1H) 1.31-1.41 (m, 1H)1.53 (br s, 2H) 1.77-1.83 (m, 1H) 2.00-2.08 (m, 1H) 2.73-2.82 (m, 1H)2.96 (t, J = 10.7 Hz, 1H) 3.30-3.38 (m, 1H) 3.53 (dd, J = 10.3, 5.9 Hz,1H) 3.72 (dd, J = 10.7, 4.9 Hz, 1H) 3.91 (ddd, J = 10.7, 4.9, 2.4 Hz,1H) 7.34-7.45 (m, 6H) 7.63-7.70 (m, 4H). 22(22c)

1H NMR (CDCl₃) δ (ppm) 1.05 (s, 9H) 1.22-1.42 (m, 2H) 1.42-1.53 (m, 9H)1.76-1.84 (m, 1H) 1.93-2.02 (m, 1H) 2.91-3.01 (m, 1H) 3.09 (t, J = 10.3Hz, 1H) 3.31-3.38 (m, 1H) 3.53 (dd, J = 10.7, 5.9 Hz, 1H) 3.72 (dd, J =10.3, 5.4 Hz, 1H) 3.83 (br s, 1H) 4.04 (ddd, J = 10.7, 4.4, 2.5 Hz, 1H)5.94 (br s, 1H) 7.34- 7.44 (m, 6H) 7.63-7.69 (m, 4H). 22(22d)

1H NMR (CDCl₃) δ (ppm) 1.03-1.25 (m, 2H) 1.50- 1.62 (m, 1H) 1.72-1.91(m, 2H) 1.91-2.09 (m, 4H) 2.38 (dd, J = 6.8, 2.0 Hz, 2H) 2.56-2.70 (m,1H) 3.66 (s, 3H) 5.29 (s, 2H) 7.22-7.29 (m, 3H) 7.42 (t, J = 7.8 Hz, 1H)9.70 (d, J = 2.0 Hz, 1H). 22(22e)

1H NMR (CDCl₃) δ (ppm) 1.35-1.48 (m, 2H) 1.85- 2.01 (m, 4H) 2.02-2.11(m, 2H) 2.57-2.72 (m, 2H) 3.66 (s, 3H) 5.29 (s, 2H) 6.00 (s, 1H) 6.27(s, 1H) 7.22-7.29 (m, 3H) 7.42 (t, J = 7.8 Hz, 1H) 9.55 (s, 1H). 22(22f)

1H NMR (CDCl₃) δ (ppm) 1.30-1.42 (m, 1H) 1.44- 1.57 (m, 1H) 1.75-1.96(m, 4H) 2.00-2.15 (m, 3H) 2.57-2.67 (m, 1H) 3.01 (d, J = 4.0 Hz, 1H)3.13 (d, J = 4.0 Hz, 1H) 3.65 (s, 3H) 5.29 (s, 2H) 7.20-7.29 (m, 3H)7.42 (t, J = 7.5 Hz, 1H) 8.87 (s, 1H).

TABLE 25 Example No. Structural formula Physicochemical data 22(22g)

1H NMR (CDCl₃) δ (ppm) 1.41-1.56 (m, 4H) 1.56- 1.64 (m, 1H) 1.76-1.82(m, 1H) 1.86-1.97 (m, 2H) 2.05-2.19 (m, 5H) 2.26-2.33 (m, 1H) 2.56-2.72(m, 2H) 3.51-3.62 (m, 2H) 3.63-3.72 (m, 4H) 4.17-4.28 (m, 2H) 5.30 (s,2H) 7.19-7.29 (m, 4H) 7.38-7.47 (m, 2H). 22(22h)

1H NMR (CDCl₃) δ (ppm) 1.41-1.55 (m, 5H) 1.75- 1.85 (m, 1H) 1.87-1.99(m, 2H) 2.02-2.19 (m, 6H) 2.21-2.32 (m, 1H) 2.39-2.47 (m, 1H) 2.55-2.74(m, 3H) 3.18-3.31 (m, 3H) 3.32-3.41 (m, 1H) 3.55-3.64 (m, 1H) 3.67 (s,3H) 4.13-4.26 (m, 2H) 5.30 (s, 2H) 7.17-7.32 (m, 4H) 7.46-7.87 (m, 2H).MS (APCI) m/z: 559 [M + H]⁺. 23(23a)

1H NMR (CDCl₃) δ (ppm) 1.11-1.17 (m, 2H) 1.24- 1.32 (m, 2H) 1.48 (s, 9H)1.94-1.97 (m, 4H) 2.20- 2.23 (m, 1H) 2.50-2.63 (m, 4H) 2.57-2.77 (m, 1H)3.72-3.75 (m, 4H) 3.97 (br s, 1H) 6.11 (br s, 1H). 23(23b)

1H NMR (D₂O) δ (ppm) 1.32-1.38 (m, 2H) 1.47- 1.54 (m, 2H) 2.15-2.20 (m,4H) 3.05-3.14 (m, 4H) 3.16-3.17 (m, 2H) 3.69-3.72 (m, 2H) 3.99-4.03 (m,2H). 23(23c)

1H NMR (CDCl₃) δ (ppm) 3.78 (s, 3H) 4.95 (s, 2H) 7.10-7.14 (m, 2H) 8.26(d, J = 5.5 Hz, 1H). 23(23d)

1H NMR (CDCl₃) δ (ppm) 3.51-4.26 (m, 2H) 4.96 (s, 2H) 7.07-7.09 (m, 1H)7.17-7.20 (m, 1H) 7.51-7.65 (m, 1H) 8.32-8.34 (m, 1H). 23(23e)

1H NMR (CDCl₃) δ (ppm) 1.53-1.73 (m, 2H) 1.78- 1.91 (m, 2H) 2.04-2.12(m, 2H) 2.14-2.23 (m, 2H) 2.39-2.50 (m, 1H) 2.61-2.70 (m, 1H) 3.64 (s,3H) 3.70 (s, 3H) 5.58 (s, 2H) 7.00-7.02 (m, 1H) 7.15- 7.18 (m, 1H) 8.36(d, J = 5.5 Hz, 1H). 23(23f)

1H NMR (CDCl₃) δ (ppm) 1.08-1.17 (m, 2H) 1.51- 2.05 (m, 7H) 2.57-2.64(m, 1H) 3.51 (t, J = 5.9 Hz, 2H) 3.62 (s, 3H) 5.55 (s, 2H) 6.98-6.99 (m,1H) 7.13 (d, J = 5.4 Hz, 1H) 8.33 (d, J = 5.4 Hz, 1H). 23(23g)

1H NMR (CDCl₃) δ (ppm) 1.37-1.48 (m, 2H) 1.70- 2.51 (m, 7H) 2.60-2.69(m, 1H) 3.65 (s, 3H) 5.59 (s, 2H) 7.01 (s, 1H) 7.16 (d, J = 4.9 Hz, 1H)8.36 (d, J = 4.9 Hz, 1H) 9.71 (s, 1H).

TABLE 26 Example No. Structural formula Physicochemical data 23(23h)

1H NMR (CDCl₃) δ (ppm) 1.13-1.22 (m, 2H) 1.61- 2.06 (m, 7H) 2.36 (dd, J= 6.6, 2.2 Hz, 2H) 2.57-2.64 (m, 1H) 3.61 (s, 3H) 5.55 (s, 2H) 6.98-6.99(m, 1H) 7.12-7.14 (m, 1H) 8.33 (d, J = 5.4 Hz, 1H) 9.76 (t, J = 2.2 Hz,1H). 23(23i)

1H NMR (CDCl₃) δ (ppm) 1.34-1.44 (m, 2H) 1.85- 1.98 (m, 4H) 2.03-2.08(m, 2H) 2.56-2.63 (m, 1H) 2.64-2.71 (m, 1H) 3.62 (s, 3H) 5.55 (s, 2H)5.98 (s, 1H) 6.25 (s, 1H) 6.99 (s, 1H) 7.13 (d, J = 5.4 Hz, 1H) 8.33 (d,J = 5.4 Hz, 1H) 9.52 (s, 1H). 23(23j)

1H NMR (CDCl₃) δ (ppm) 1.30-1.39 (m, 1H) 1.44- 1.53 (m, 1H) 1.76-1.93(m, 4H) 2.00-2.12 (m, 3H) 2.58-2.64 (m, 1H) 2.98 (d, J = 4.4 Hz, 1H)3.10 (d, J = 4.4 Hz, 1H) 3.61 (s, 3H) 5.55 (s, 2H) 6.98-6.99 (m, 1H)7.12-7.14 (m, 1H) 8.33 (d, J = 4.9 Hz, 1H) 8.85 (s, 1H). 23(23k)

1H NMR (CDCl₃) δ (ppm) 1.38-2.41 (m, 17H) 2.53- 2.70 (m, 6H) 3.65 (s,3H) 3.72-3.75 (m, 4H) 4.00- 4.13 (m, 1H) 5.59 (s, 2H) 7.01 (s, 1H) 7.16(d, J = 5.0 Hz, 1H) 7.22 (s, 1H) 7.38 (s, 1H) 8.36 (d, J = 5.0 Hz, 1H).MS (APCI) m/z: 574 [M + H]⁺. 24(24a)

1H NMR (CDCl₃) δ (ppm) 5.03 (s, 1H) 5.34 (s, 2H) 7.38-7.44 (m, 5H).24(24b)

1H NMR (CDCl₃) δ (ppm) 1.02-1.14 (m, 4H) 1.71- 1.78 (m, 2H) 1.78-1.87(m, 1H) 1.96-2.07 (m, 2H) 3.33 (s, 4H) 3.39-3.50 (m, 1H) 4.73 (s, 4H)5.08 (s, 2H) 7.27-7.40 (m, 5H). 24(24c)

1H NMR (CDCl₃) δ (ppm) 0.96-1.11 (m, 4H) 1.70- 1.76 (m, 2H) 1.80-1.87(m, 3H) 2.58-2.67 (m, 1H) 3.33 (s, 4H) 4.73 (s, 4H). 24(24d)

1H NMR (CDCl₃) δ (ppm) 0.92-1.13 (m, 4H) 1.70- 1.79 (m, 2H) 1.80-1.92(m, 3H) 2.73-2.85 (m, 1H) 3.33 (s, 4H) 3.98 (br s, 1H) 4.73 (s, 4H) 5.13(s, 2H) 6.19 (br s, 1H) 7.32-7.40 (m, 5H). 24(24e)

1H NMR (CDCl₃) δ (ppm) 1.04-1.28 (m, 4H) 1.76- 1.87 (m, 2H) 2.00-2.21(m, 6H) 2.56-2.63 (m, 1H) 3.48-3.79 (m, 4H) 4.71-4.79 (m, 4H) 5.57-5.93(m, 3H).

TABLE 27 Ex- ample No. Structural formula Physicochemical data 24(24f)

1H NMR (CDCl₃) δ (ppm) 1.09-1.23 (m, 2H) 1.42-1.54 (m, 2H) 1.69-1.81 (m,2H) 1.85- 2.20 (m, 11H) 2.64-2.66 (m, 2H) 3.37 (s, 4H) 3.65 (s, 3H)3.98-4.06 (m, 1H) 4.75 (s, 4H) 5.59 (s, 2H) 7.01-7.02 (m, 1H) 7.15-7.17(m, 1H) 7.21 (s, 1H) 7.37 (s, 1H) 8.36 (d, J = 5.4 Hz, 1H). MS (APCI)m/z: 586 [M + H]⁺. 25(25a)

1H NMR (CDCl₃) δ (ppm) 1.29-1.39 (m, 2H) 1.42-1.53 (m, 2H) 1.80-1.99 (m,4H) 2.03- 2.25 (m, 9H) 2.58-2.73 (m, 2H) 3.66 (s, 3H) 4.02-4.11 (m, 1H)4.61-4.69 (m, 1H) 5.10 (s, 2H) 5.59 (s, 2H) 7.02 (s, 1H) 7.16 (d, J =5.4 Hz, 1H) 7.22 (s, 1H) 7.30-7.39 (m, 6H) 8.36 (d, J = 5.4 Hz, 1H).25(25b)

1H NMR (CDCl₃) δ (ppm) 1.25-1.35 (m, 2H) 1.43-1.54 (m, 2H) 1.75-2.24 (m,14H) 2.59- 2.73 (m, 3H) 3.66 (s, 3H) 4.02-4.09 (m, 1H) 5.59 (s, 2H) 7.02(s, 1H) 7.16 (d, J = 5.4 Hz, 1H) 7.23 (s, 1H) 7.38 (s, 1H) 8.36 (d, J =5.4 Hz, 1H). 25(25c)

1H NMR (CDCl₃) δ (ppm) 2.53-2.65 (m, 4H) 3.66 (s, 4H) 4.52 (t, J = 8.0Hz, 2H). 25(25d)

1H NMR (CDCl₃) δ (ppm) 1.16-1.26 (m, 2H) 1.42-1.53 (m, 2H) 1.70-1.80 (m,2H) 1.89- 2.19 (m, 11H) 2.58-2.72 (m, 2H) 2.88 (t, J = 7.5 Hz, 2H)3.11-3.16 (m, 2H) 3.64-3.68 (m, 2H) 3.65 (s, 3H) 3.99-4.07 (m, 1H) 4.53(t, J = 7.5 Hz, 2H) 5.59 (s, 2H) 7.01-7.02 (m, 1H) 7.15-7.17 (m, 1H)7.21 (s, 1H) 7.37 (s, 1H) 8.36 (d, J = 5.1 Hz, 1H). MS (APCI) m/z: 586[M + H]⁺. 26(26a)

1H NMR (CDCl₃) δ (ppm) 1.69-1.82 (m, 2H) 1.97-2.09 (m, 2H) 2.23-2.35 (m,2H) 2.45- 2.56 (m, 2H) 3.36-3.44 (m, 1H) 4.12 (br s, 1H) 5.16 (s, 2H)6.34 (br s, 1H) 7.32-7.42 (m, 5H). 26(26b)

1H NMR (CDCl₃) δ (ppm) 1.07-1.17 (m, 2H) 1.18-1.30 (m, 2H) 1.84-2.00 (m,5H) 2.11 (t, J = 6.9 Hz, 2H) 2.57 (t, J = 7.3 Hz, 2H) 2.76- 2.87 (m, 1H)2.89 (s, 2H) 3.99 (br s, 1H) 4.61 (s, 4H) 5.13 (s, 2H) 6.22 (br s, 1H)7.31-7.39 (m, 5H). 26(26c)

1H NMR (CDCl₃) δ (ppm) 1.36-1.53 (m, 4H) 1.75-1.85 (m, 2H) 1.89-1.99 (m,2H) 2.04- 2.23 (m, 11H) 2.58-2.73 (m, 4H) 2.93 (s, 2H) 3.65 (s, 3H)4.01-4.09 (m, 1H) 4.63 (s, 4H) 5.59 (s, 2H) 7.01-7.02 (m, 1H) 7.15-7.17(m, 1H) 7.23 (s, 1H) 7.38 (s, 1H) 8.36 (d, J = 5.4 Hz, 1H). MS (APCI)m/z: 600 [M + H]⁺.

TABLE 28 Ex- ample No. Structural formula Physicochemical data 27(27a)

1H NMR (CDCl₃) δ (ppm) 1.33-1.42 (m, 2H) 1.44- 1.52 (m, 2H) 1.62-1.69(m, 2H) 1.74-1.80 (m, 2H) 2.01-2.06 (m, 1H) 2.07 (t, J = 6.9 Hz, 2H)3.15-3.20 (m, 4H) 3.77 (t, J = 6.9 Hz, 2H) 3.81 (s, 2H) 3.92 (s, 4H).27(27b)

1H NMR (CDCl₃) δ (ppm) 1.63-1.72 (m, 2H) 1.83- 1.90 (m, 2H) 2.10 (t, J =7.3 Hz, 2H) 2.19-2.26 (m, 2H) 2.41-2.46 (m, 1H) 2.48-2.55 (m, 2H)3.21-3.26 (m, 4H) 3.80 (t, J = 7.3 Hz, 2H) 3.83 (s, 2H). 27(27c)

1H NMR (CDCl₃) δ (ppm) 0.97-1.13 (m, 4H) 1.73- 1.79 (m, 2H) 1.84-1.95(m, 3H) 2.08 (t, J = 6.9 Hz, 2H) 2.76-2.84 (m, 1H) 3.16-3.22 (m, 4H)3.77 (t, J = 6.9 Hz, 2H) 3.80 (s, 2H) 3.98 (br s, 1H) 5.13 (s, 2H) 6.22(br s, 1H) 7.30-7.39 (m, 5H). 27(27d)

1H NMR (CDCl₃) δ (ppm) 1.16-1.26 (m, 2H) 1.43- 1.53 (m, 2H) 1.71-1.81(m, 2H) 1.88-1.99 (m, 4H) 2.02-2.12 (m, 3H) 2.10 (t, J = 6.9 Hz, 2H)2.13-2.20 (m, 4H) 2.58-2.73 (m, 2H) 3.21-3.26 (m, 4H) 3.65 (s, 3H) 3.79(t, J = 6.9 Hz, 2H) 3.83 (s, 2H) 4.00-4.07 (m, 1H) 5.59 (s, 2H)7.01-7.02 (m, 1H) 7.15-7.17 (m, 1H) 7.22 (s, 1H) 7.37 (s, 1H) 8.36 (d, J= 5.1 Hz, 1H). MS (APCI) m/z: 600 [M + H]⁺. 28(28a)

1H NMR (CDCl₃) δ (ppm) 1.11 (s, 9H) 1.82-1.92 (m, 1H) 2.13 (dt, J =15.1, 6.6 Hz, 1H) 2.18-2.27 (m, 1H) 2.38 (dt, J = 15.1, 6.6 Hz, 1H) 3.80(td, J = 6.6, 4.9 Hz, 1H) 4.42-4.51 (m, 1H) 4.86-4.97 (m, 1H) 7.33- 7.50(m, 6H), 7.62-7.73 (m, 6H), 7.76-7.82 (m, 2H). 28(28b)

1H NMR (CDCl₃) δ (ppm) 1.08 (s, 9H) 1.74-1.83 (m, 1H) 1.84-1.95 (m, 1H)2.31-2.40 (m, 1H) 2.40-2.50 (m, 1H) 3.20 (td, J = 6.8, 3.9 Hz, 1H)4.11-4.16 (m, 1H) 4.90-5.01 (m, 1H) 7.32-7.47 (m, 6H) 7.62-7.71 (m, 6H)7.76-7.84 (m, 2H). 28(28c)

1H NMR (CDCl₃) δ (ppm) 1.10 (s, 9H) 1.73-1.88 (m, 2H) 2.06-2.17 (m, 1H)2.72-2.90 (m, 1H) 4.21-4.30 (m, 1H) 4.33 (s, 1H) 5.01-5.19 (m, 3H) 6.37(d, J = 8.3 Hz, 1H) 7.28-7.46 (m, 11H) 7.64-7.77 (m, 6H) 7.77-7.85 (m,2H).

TABLE 29 Ex- ample No. Structural formula Physicochemical data 28(28d)

1H NMR (CDCl₃) δ (ppm) 1.00 (s, 9H) 1.20-1.33 (m, 1H) 1.41-1.56 (m, 1H)1.80-1.90 (m, 1H) 2.27-2.41 (m, 1H) 3.57-3.71 (m, 1H) 4.00-4.13 (m, 1H)4.18-4.26 (m, 1H) 5.04 (s, 2H) 5.56 (d, J = 7.3 Hz, 1H) 7.24-7.45 (m,11H) 7.54-7.72 (m, 4H). 28(28e)

1H NMR (CDCl₃) δ (ppm) 1.44-2.28 (m, 12H) 2.30- 2.50 (m, 2H) 2.60-2.75(m, 4H) 3.26 (t, J = 7.6 Hz, 4H) 3.65 (s, 3H) 4.15-4.18 (m, 1H)4.82-4.95 (m, 1H) 5.58 (s, 2H) 7.02 (s, 1H) 7.16 (d, J = 5.4 Hz, 1H)7.35 (s, 1H) 7.37 (s, 1H) 8.36 (d, J = 5.4 Hz, 1H). MS (APCI) m/z: 546[M + H]⁺. 29

1H NMR (CDCl₃) δ (ppm) 1.13-1.27 (m, 2H) 1.42- 1.54 (m, 2H) 1.71-1.82(m, 2H) 1.87-1.99 (m, 4H) 2.05-2.20 (m, 7H) 2.58-2.74 (m, 2H) 3.14 (s,4H) 3.66 (s, 3H) 3.84 (s, 4H) 3.99-4.08 (m, 1H) 5.58 (s, 2H) 7.02 (d, J= 1.8 Hz, 1H) 7.17 (dd, J = 5.5, 1.8 Hz, 1H) 7.22 (s, 1H) 7.38 (s, 1H)8.36 (d, J = 5.5 Hz, 1H). MS (APCI) m/z: 604 [M + H]⁺. 30(30a)

1H NMR (CDCl₃) δ (ppm) 1.63-1.65 (m, 2H) 1.85- 1.86 (m, 2H) 2.03-2.07(m, 2H) 2.22-2.24 (m, 2H) 2.42-2.51 (m, 3H) 3.17-3.24 (m, 4H). 30(30b)

1H NMR (CDCl₃) δ (ppm) 1.27-1.32 (m, 4H) 1.39 (s, 9H) 1.73-1.82 (m, 4H)1.92-1.95 (m, 1H) 2.40-2.43 (m, 1H) 2.62-2.65 (m, 1H) 2.96 (s, 1H) 3.32(s, 2H) 3.62-3.69 (m, 2H) 4.07-4.08 (m, 1H) 8.20 (br s, 1H). 30(30c)

1H NMR (D₂O) δ (ppm) 1.19-1.31 (m, 4H) 2.08- 2.47 (m, 6H) 3.04-3.11 (m,2H) 4.04 (br s, 4H). 30(30d)

1H NMR (CDCl₃) δ (ppm) 1.03 (s, 9H) 1.09-1.20 (m, 2H) 1.77-1.86 (m, 2H)1.89-1.94 (m, 2H) 1.96-2.04 (m, 3H) 2.35 (dd, J = 6.8, 2.0 Hz, 2H)2.51-2.59 (m, 1H) 3.57 (s, 3H) 4.84 (s, 2H) 7.35-7.39 (m, 4H) 7.40-7.44(m, 2H) 7.61-7.65 (m, 4H) 9.76 (t, J = 2.2 Hz, 1H). 30(30e)

1H NMR (CDCl₃) δ (ppm) 1.03 (s, 9H) 1.32-1.42 (m, 2H) 1.83-1.96 (m, 4H)2.00-2.05 (m, 2H) 2.54-2.65 (m, 2H) 3.58 (s, 3H) 4.84 (s, 2H) 5.97 (s,1H) 6.25 (s, 1H) 7.35-7.44 (m, 6H) 7.61-7.65 (m, 4H) 9.52 (s, 1H).

TABLE 30 Example No. Structural formula Physicochemical data 30(30f)

1H NMR (CDCl₃) δ (ppm) 1.03 (s, 9H) 1.28-1.37 (m, 1H) 1.42-1.51 (m, 1H)1.72-1.91 (m, 4H) 1.98-2.03 (m, 2H) 2.04-2.12 (m, 1H) 2.51-2.60 (m, 1H)2.97 (d, J = 4.4 Hz, 1H) 3.09 (d, J = 4.4 Hz, 1H) 3.56 (s, 3H) 4.84 (s,2H) 7.35-7.38 (m, 4H) 7.40-7.44 (m, 2H) 7.61-7.64 (m, 4H) 8.85 (s, 1H).30(30g)

1H NMR (CDCl₃) δ (ppm) 1.06 (s, 9H) 1.13-1.23 (m, 2H) 1.41-1.51 (m, 2H)1.72-2.19 (m, 15H) 2.57- 2.68 (m, 2H) 3.23 (t, J = 6.9 Hz, 4H) 3.61 (s,3H) 4.00-4.07 (m, 1H) 4.87 (s, 2H) 7.22 (s, 1H) 7.36- 7.47 (m, 7H)7.63-7.68 (m, 4H). 30(30h)

1H NMR (CDCl₃) δ (ppm) 1.09-1.20 (m, 2H) 1.40- 1.51 (m, 2H) 1.70-2.18(m, 15H) 2.54-2.69 (m, 2H) 3.21 (t, J = 6.9 Hz, 4H) 3.62-3.70 (m, 1H)3.68 (s, 3H) 3.98-4.06 (m, 1H) 4.76 (s, 2H) 7.21 (s, 1H) 7.36 (s, 1H).30(30i)

1H NMR (CDCl₃) δ (ppm) 1.12-1.22 (m, 2H) 1.42- 1.52 (m, 2H) 1.71-2.19(m, 15H) 2.58-2.72 (m, 2H) 3.21 (t, J = 6.9 Hz, 4H) 3.67 (s, 3H) 3.92(s, 3H) 3.99- 4.07 (m, 1H) 5.29 (s, 2H) 7.22 (s, 1H) 7.24-7.26 (m, 1H)7.36-7.40 (m, 2H) 7.67-7.70 (m, 2H). MS (APCI) m/z: 533 [M + H]⁺.31(31a)

1H NMR (CDCl₃) δ (ppm) 1.06 (s, 9H) 1.11-1.23 (m, 2H) 1.40-1.51 (m, 2H)1.69-1.82 (m, 2H) 1.85-2.01 (m, 6H) 2.02-2.10 (m, 1H) 2.11-2.20 (m, 4H)2.55- 2.70 (m, 2H) 3.37 (s, 4H) 3.61 (s, 3H) 3.97-4.06 (m, 1H) 4.75 (s,4H) 4.87 (s, 2H) 7.21 (s, 1H) 7.36- 7.48 (m, 7H) 7.63-7.69 (m, 4H).31(31b)

1H NMR (CDCl₃) δ (ppm) 1.11-1.23 (m, 2H) 1.41- 1.52 (m, 2H) 1.65-2.08(m, 10H) 2.09-2.20 (m, 4H) 2.55-2.70 (m, 2H) 3.37 (s, 4H) 3.67 (s, 3H)3.96- 4.05 (m, 1H) 4.75 (s, 4H) 4.78 (s, 2H) 7.21 (s, 1H) 7.36 (s, 1H).31(31c)

1H NMR (CDCl₃) δ (ppm) 1.11-1.24 (m, 2H) 1.40- 1.52 (m, 2H) 1.70-1.82(m, 2H) 1.85-2.02 (m, 5H) 2.03-2.11 (m, 2H) 2.11-2.20 (m, 4H) 2.56-2.72(m, 2H) 3.37 (s, 4H) 3.67 (s, 3H) 3.92 (m, 3H) 3.97- 4.06 (m, 1H) 4.75(s, 4H) 5.29 (s, 2H) 7.21 (s, 1H) 7.23-7.28 (m, 1H) 7.34-7.42 (m, 2H)7.65-7.72 (m, 2H). MS (APCI) m/z: 575 [M + H]⁺. 32(32a)

1H NMR (CDCl₃) δ (ppm) 1.06 (s, 9H) 1.16-1.27 (m, 2H) 1.41-1.51 (m, 2H)1.71-2.19 (m, 15H) 2.57-2.68 (m, 2H) 3.20-3.27 (m, 4H) 3.61 (s, 3H),3.79 (t, J = 6.1 Hz, 2H) 3.83 (s, 2H) 3.99-4.08 (m, 1H) 4.87 (s, 2H)7.22 (s, 1H) 7.37-7.47 (m, 7H) 7.64-7.68 (m, 4H).

TABLE 31 Ex- ample No. Structural formula Physicochemical data 32(32b)

1H NMR (CDCl₃) δ (ppm) 1.14-1.25 (m, 2H) 1.40- 1.51 (m, 2H) 1.70-2.19(m, 15H) 2.55-2.69 (m, 2H) 3.19-3.28 (m, 4H) 3.61-3.69 (m, 1H) 3.67 (s,3H) 3.79 (t, J = 6.9 Hz, 2H) 3.82 (s, 2H) 3.98-4.06 (m, 1H) 4.76 (s, 2H)7.21 (s, 1H) 7.36 (s, 1H). 32(32c)

1H NMR (CDCl₃) δ (ppm) 1.09-2.44 (m, 28H) 2.56- 2.72 (m, 2H) 3.19-3.42(m, 5H) 3.59-3.69 (m, 3H) 3.76-3.87 (m, 4H) 3.98-4.09 (m, 1H) 4.63-4.76(m, 2H) 7.22 (s, 1H) 7.38 (s, 1H). MS (ESI) m/z: 605 [M + H]⁺. 33(33a)

1H NMR (CDCl₃) δ (ppm) 1.16-1.26 (m, 2H) 1.44- 1.54 (m, 2H) 1.72-1.82(m, 2H) 1.88-2.21 (m, 13H) 2.60-2.67 (m, 1H) 2.71-2.78 (m, 1H) 3.21-3.26(m, 4H) 3.79 (t, J = 6.9 Hz, 2H) 3.83 (s, 2H) 3.91 (s, 3H) 3.99-4.07 (m,1H) 7.22 (s, 1H) 7.38 (s, 1H) 10.08 (s, 1H). 33(33b)

1H NMR (CDCl₃) δ (ppm) 1.16-1.26 (m, 2H) 1.41- 1.52 (m, 2H) 1.71-1.81(m, 2H) 1.88-1.97 (m, 4H) 2.02-2.20 (m, 7H) 2.10 (t, J = 6.9 Hz, 2H)2.58-2.70 (m, 2H) 3.21-3.26 (m, 4H) 3.57 (s, 3H) 3.79 (t, J = 6.9 Hz,2H) 3.83 (s, 2H) 3.99-4.07 (m, 1H) 5.63 (dd, J = 11.5, 1.5 Hz, 1H) 6.28(dd, J = 17.6, 1.5 Hz, 1H) 6.58 (dd, J = 17.6, 11.5 Hz, 1H) 7.22 (s, 1H)7.37 (s, 1H). 33(33c)

1H NMR (CDCl₃) δ (ppm) 1.15-1.26 (m, 2H) 1.40- 1.50 (m, 2H) 1.70-1.95(m, 6H) 1.99-2.19 (m, 9H) 2.55-2.65 (m, 2H) 3.20-3.27 (m, 6H) 3.49 (s,3H) 3.79 (t, J = 6.9 Hz, 2H) 3.83 (s, 2H) 3.99-4.07 (m, 1H) 4.47 (t, J =6.5 Hz, 2H) 6.21 (t, J = 6.9 Hz, 1H) 7.21 (s, 1H) 7.36 (s, 1H) 7.75 (d,J = 6.9 Hz, 1H) 7.88 (dd, J = 6.9, 1.9 Hz, 1H). MS (APCI) m/z: 614 [M +H]⁺. 34(34a)

1H NMR (CDCl₃) δ (ppm) 1.48 (s, 9H) 1.84-1.95 (m, 2H) 2.09-2.17 (m, 2H)2.94-3.04 (m, 2H) 3.12-3.22 (m, 1H) 3.97 (s, 3H) 4.11-4.21 (m, 2H) 8.11(d, J = 8.5 Hz, 2H) 8.18 (d, J = 8.5 Hz, 2H). 34(34b)

1H NMR (DMSO-d₆) δ (ppm) 1.42 (s, 9H) 1.62-1.73 (m, 2H) 2.03-2.10 (m,2H) 2.93-3.07 (m, 2H) 3.26- 3.33 (m, 1H) 3.90-3.97 (m, 2H) 8.10-8.15 (m,4H) 13.38 (s, 1H). 34(34c)

1H NMR (CDCl₃) δ (ppm) 1.48 (s, 9H) 1.84-1.95 (m, 2H) 2.09-2.16 (m, 2H)2.94-3.03 (m, 2H) 3.06 (d, J = 4.9 Hz, 3H) 3.14-3.21 (m, 1H) 4.11-4.19(m, 2H) 6.19 (d, J = 4.9 Hz, 1H) 7.90 (d, J = 8.5 Hz, 2H) 8.11 (d, J =8.5 Hz, 2H).

TABLE 32 Example No. Structural formula Physicochemical data 34(34d)

1H NMR (CDCl₃) δ (ppm) 1.48 (s, 9H) 1.83-1.95 (m, 2H) 2.09-2.18 (m, 2H)2.93-3.04 (m, 2H) 3.13-3.21 (m, 1H) 3.40 (d, J = 4.9 Hz, 3H) 4.10-4.21(m, 2H) 7.74-7.80 (m, 1H) 7.88 (d, J = 8.5 Hz, 2H) 8.05 (d, J = 8.5 Hz,2H). 34(34e)

1H NMR (CDCl₃) δ (ppm) 1.49 (s, 9H) 1.84-1.96 (m, 2H) 2.11-2.19 (m, 2H)2.95-3.05 (m, 2H) 3.15-3.24 (m, 1H) 3.86 (s, 3H) 4.12-4.21 (m, 2H) 5.41(s, 2H) 7.27-7.34 (m, 3H) 7.46 (t, J = 7.9 Hz, 1H) 7.85 (d, J = 8.5 Hz,2H) 8.20 (d, J = 8.5 Hz, 2H). 34(34f)

1H NMR (CDCl₃) δ (ppm) 1.86-2.00 (m, 3H) 2.11- 2.18 (m, 2H) 2.76-2.85(m, 2H) 3.12-3.27 (m, 3H) 3.85 (s, 3H) 5.41 (s, 2H) 7.28-7.33 (m, 3H)7.46 (t, J = 7.9 Hz, 1H) 7.85 (d, J = 8.5 Hz, 2H) 8.20 (d, J = 8.5 Hz,2H). 34(34g)

1H NMR (CDCl₃) δ (ppm) 2.00-2.21 (m, 6H) 2.34 (s, 3H) 2.91-3.06 (m, 3H)3.85 (s, 3H) 5.41 (s, 2H) 7.28-7.33 (m, 3H) 7.46 (t, J = 7.9 Hz, 1H)7.85 (d, J = 8.5 Hz, 2H) 8.20 (d, J = 8.5 Hz, 2H). MS (APCI) m/z: 499[M + H]⁺. 35(35a)

1H NMR (CDCl₃) δ (ppm) 1.55-1.65 (m, 2H) 1.80- 1.90 (m, 2H) 2.06-2.11(m, 2H) 2.16-2.22 (m 2H) 2.42-2.50 (m, 1H) 2.62-2.70 (m, 1H) 3.67 (s,3H) 3.72 (s, 3H) 5.28 (s, 2H) 6.96-7.05 (m, 3H) 7.23- 7.26 (m, 1H).35(35b)

1H NMR (CDCl₃) δ (ppm) 1.15-2.16 (m, 10H) 2.60- 2.68 (m, 1H) 3.56 (t, J= 5.7 Hz, 2H) 3.67 (s, 3H) 5.26 (s, 2H) 6.97-7.05 (m, 3H) 7.23-7.26 (m,1H). 35(35c)

1H NMR (CDCl₃) δ (ppm) 1.40-2.28 (m, 8H) 2.35- 2.45 (m, 1H) 2.62-2.70(m, 1H) 3.68 (s, 3H) 5.27 (s, 2H) 6.96-7.05 (m, 3H) 7.24-7.33 (m, 1H)8.64- 8.66 (m, 1H). 35(35d)

1H NMR (CDCl₃) δ (ppm) 1.38-2.08 (m, 9H) 2.30- 2.41 (m, 1H) 2.60-2.68(m, 1H) 3.67 (s, 3H) 5.27 (s, 2H) 6.96-7.06 (m, 3H) 7.23-7.26 (m, 1H)7.41 (d, J = 5.3 Hz, 1H). 35(35e)

1H NMR (CDCl₃) δ (ppm) 1.48 (s, 9H) 1.50-2.25 (m, 13H) 2.70-2.76 (m, 1H)2.85-2.91 (m, 1H) 3.23 (t, J = 10.3 Hz, 1H) 3.69 (s, 3H) 4.19-4.23 (m,1H) 4.39 (br s, 1H) 4.49-4.51 (m, 1H) 5.27 (s, 2H) 6.14 (s, 1H)6.97-7.06 (m, 3H) 7.23-7.26 (m, 1H).

TABLE 33 Example No. Structural formula Physicochemical data 35(35f)

1H NMR (CDCl₃) δ (ppm) 1.35-2.20 (m, 14H) 2.63- 2.72 (m, 1H) 2.80-2.97(m, 2H) 3.17 (t, J = 10.7 Hz, 1H) 3.66 (s, 3H) 4.04-4.08 (m, 1H)4.43-4.47 (m, 1H) 5.24 (s, 2H) 6.09 (s, 1H) 6.95-7.03 (m, 3H) 7.20-7.24(m, 1H). 35(35g)

1H NMR (CDCl₃) δ (ppm) 1.43-2.38 (m, 14H) 2.67- 2.72 (m, 1H) 2.82-2.87(m, 1H) 3.20-3.27 (m, 5H) 2.84-2.89 (m, 1H) 3.66 (s, 3H) 3.98-4.01 (m,1H) 4.42-4.45 (m, 1H) 5.24 (s, 2H) 6.09 (s, 1H) 6.94- 7.03 (m, 3H)7.21-7.30 (m, 1H). MS (APCI) m/z: 512 [M + H]⁺. 36(36a)

1H NMR (CDCl₃) δ (ppm) 1.33-1.49 (m, 21H) 1.51- 1.65 (m, 2H) 1.93-2.04(m, 2H) 2.78 (d, J = 6.4 Hz, 3H) 3.13-3.22 (m, 1H) 3.29-3.38 (m, 1H)3.63-3.76 (m, 2H) 5.68-5.69 (m, 1H). 36(36b)

1H NMR (DMSO-d₆) δ (ppm) 1.14 (d, J = 4.4 Hz, 6H) 1.38-1.48 (m, 2H)1.53-1.69 (m, 9H) 1.90-1.97 (m, 4H) 2.15 (s, 3H) 2.25-2.49 (m, 5H)2.71-2.86 (m, 4H) 3.54 (s, 3H) 5.75 (t, J = 6.4 Hz, 1H) 6.82-6.85 (m,3H) 7.19 (q, J = 8.0 Hz, 1H). MS (ESI) m/z: 480 [M + H]⁺.

1. A compound of formula (1) or a pharmacologically acceptable saltthereof:

wherein the symbols in the formula are defined below: A: a 5-to6-membered aromatic heterocycle, a 4-to 7-membered saturatedheterocycle, benzene, cyclohexane or a ring having the followingstructure, wherein each of the rings has at least one bond;

E: —CH₂—, —O—, or a single bond; G: a 5-membered aromatic heterocycle,wherein the ring has at least two bonds; if the ring has a nitrogenatom(s), then at least one of the nitrogen atom(s) is next to an atomthat is attached to a right-hand portion, wherein the right-hand portionrefers to the following portion in the compound of formula (1):

wherein the symbols indicating the respective substituents are the sameas defined above; X: any ring selected from the following rings, whereinthe any ring includes a ring condensed with additional atoms to form abicyclic ring, and wherein the any ring has at least two bonds:

wherein A⁴, A⁵: each independently, —CH═ or —N═, A⁶, A⁷: eachindependently, —CH₂—, —O—, or —NH—, m¹, m², m³: each independently, 0,1, 2, or 3; J: a 5-membered aromatic heterocycle wherein J is optionallycondensed with X to have a bicyclic structure, or a 5-memberedunsaturated heterocycle, wherein the ring has at least two bonds; Y: anamino group optionally substituted with 1-2 groups independentlyselected from Substituent group Y¹, a phenyl group optionallysubstituted with 1-3 groups independently selected from Substituentgroup Y¹, a C3-C8 cycloalkyl group optionally substituted with 1-3groups independently selected from Substituent group Y¹, wherein theC3-C8 cycloalkyl group optionally has the following bridged structures:

a C3-C8 cycloalkenyl group optionally substituted with 1-3 groupsindependently selected from Substituent group Y¹, a 4-to 7-memberedsaturated heterocyclic group optionally substituted with 1-3 groupsindependently selected from Substituent group Y¹, a 4- to 7-memberedunsaturated heterocyclic group optionally substituted with 1-3 groupsindependently selected from Substituent group Y¹, or a group formed byattachment to R⁷, optionally substituted with 1-3 groups independentlyselected from Substituent group Y¹, selected from the following:

Substituent group Y¹: a hydroxyl group, an amino group optionallysubstituted with 1-2 groups independently selected from Substituentgroup Y², a cyano group, a halogen atom, a C1-C6 alkyl group optionallysubstituted with 1-3 groups independently selected from Substituentgroup Y², a C1-C6 alkoxy group optionally substituted with 1-3 groupsindependently selected from Substituent group Y², a 4- to 7-memberedsaturated heterocyclic group optionally substituted with 1-3 groupsindependently selected from Substituent group Y², and any groupoptionally substituted with 1-3 groups independently selected fromSubstituent group Y², selected from the following:

Substituent group Y²: a hydroxyl group, a halogen atom, a C1-C6 alkylgroup optionally substituted with 1-3 groups independently selected fromSubstituent group Y³, a C1-C6 alkoxy group optionally substituted with1-3 groups independently selected from Substituent group Y³, an aminogroup optionally substituted with 1-2 groups independently selected fromSubstituent group Y³, a 4- to 7-membered saturated heterocyclic groupoptionally substituted with 1-3 groups independently selected fromSubstituent group Y³, and any group optionally substituted with 1-3groups independently selected from Substituent group Y³, selected fromthe following:

Substituent group Y³: a hydroxyl group, a halogen atom, a cyano group, aC1-C6 alkyl group optionally substituted with 1-3 groups independentlyselected from Substituent group Y⁴, a C1-C6 alkoxy group optionallysubstituted with 1-3 groups independently selected from Substituentgroup Y⁴, and any group optionally substituted with 1-3 groupsindependently selected from Substituent group Y⁴, selected from thefollowing:

Substituent group Y⁴: a fluorine atom; R¹, R², R³: each independently, ahydrogen atom, a carboxyl group, a cyano group, a halogen atom, a C1-C6alkyl group, a C1-C6 alkoxy group, a C3-C8 cycloalkyl group, a C3-C8cycloalkoxy group, a hydroxy C-C6 alkyl group, a halo C1-C6 alkyl group,a halo C-C6 alkoxy group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylC3-C8 cycloalkyl group, a C3-C8 cycloalkyl C1-C6 alkoxy group, a 4- to7-membered unsaturated heterocyclic group, a C-C6 alkyl 4- to 7-memberedunsaturated heterocyclic group, a di(C1-C6 alkyl)amino 4- to 7-memberedunsaturated heterocyclic group, a 4- to 7-membered unsaturatedheterocyclic carbonyl group, or a C3-C8 cycloalkylcarbonyl group; R⁴: ahydrogen atom, a C1-C6 alkyl group, a halo C1-C6 alkyl group, or a groupformed by attachment to R^(6c) or R^(6d), selected from the following:

wherein m⁴ is 0, 1, or 2, and R^(m4) is a hydrogen atom or a methylgroup, R⁵: a hydrogen atom, a halogen atom, or a C1-C6 alkyl group;R^(6a), R^(6b), R^(6c), R^(6d): each independently, a hydrogen atom or aC1-C6 alkyl group; R⁷: a single bond, a hydrogen atom, or a methylgroup; R⁸: a hydrogen atom or a methyl group; and n¹, n², n³: eachindependently, 0, 1, or
 2. 2. A compound or a pharmacologicallyacceptable salt thereof according to claim 1, wherein A is a 6-memberedaromatic heterocycle or benzene, each of which has at least onesubstituent.
 3. A compound or a pharmacologically acceptable saltthereof according to claim 1, wherein A is pyridine or benzene, each ofwhich has at least one substituent.
 4. A compound or a pharmacologicallyacceptable salt thereof according to claim 1, wherein each of R^(6a),R^(6b), R^(6c) is a hydrogen atom, R^(6d) is a hydrogen atom or a methylgroup, n¹ is 0, n² is 1, and E is —O—.
 5. A compound or apharmacologically acceptable salt thereof according to claim 1, whereinG is the following:


6. A compound or a pharmacologically acceptable salt thereof accordingto claim 1, wherein X is benzene, pyridine or cyclohexane, each of whichhas at least two bonds.
 7. A compound or a pharmacologically acceptablesalt thereof according to claim 1, wherein J is a ring selected from thefollowing ring group:

and R⁷ is a hydrogen atom, or a single bond.
 8. A compound or apharmacologically acceptable salt thereof according to claim 1, whereinR¹, R², and R³ are, each independently, a hydrogen atom, a carboxylgroup, a cyano group, a fluorine atom, a chlorine atom, a methyl group,an isopropyl group, a t-butyl group, a trifluoromethyl group, atrifluoromethoxy group, a cyclopropylmethoxy group, a1,1-difluoro-2-methylpropyl group, a 1,1-difluoro-2,2-dimethylpropylgroup, a 1-methyl-1-cyclobutyl group, a methoxycarbonyl group, anethoxycarbonyl group, an isopropoxycarbonyl group, a1-hydroxy-1-methylethyl group, an azetidine-1-carbonyl group, a3-methyloxetan-3-yl group, a 4,5-dihydrooxazol-2-yl group, or acyclopropylcarbonyl group.
 9. A compound of formula (1′) or apharmacologically acceptable salt thereof:

wherein the symbols in the formula are defined below: R¹: a hydrogenatom, a carboxyl group, a cyano group, a fluorine atom, a chlorine atom,a methyl group, an isopropyl group, a t-butyl group, a trifluoromethylgroup, a trifluoromethoxy group, a cyclopropylmethoxy group, a1,1-difluoro-2-methylpropyl group, a 1,1-difluoro-2,2-dimethylpropylgroup, a 1-methyl-1-cyclobutyl group, a methoxycarbonyl group, anethoxycarbonyl group, an isopropoxycarbonyl group, a1-hydroxy-1-methylethyl group, an azetidine-1-carbonyl group, a3-methyloxetan-3-yl group, a 4,5-dihydrooxazol-2-yl group, or acyclopropylcarbonyl group; R^(6d): a hydrogen atom or a methyl group;A¹: ═N—, or ═CH—; X: benzene, pyridine or cyclohexane, each of which hastwo substituents; J: any ring selected from the following ring group:

Y: an amino group optionally substituted with 1-2 groups independentlyselected from Substituent group Y¹, a phenyl group optionallysubstituted with 1-3 groups independently selected from Substituentgroup Y¹, any group optionally substituted with 1-3 groups independentlyselected from Substituent group Y¹, selected from the following: acyclobutyl group, a cyclopentyl group, a cyclohexyl group,

a cyclohexenyl group optionally substituted with 1-3 groupsindependently selected from Substituent group Y¹, any group optionallysubstituted with 1-3 groups independently selected from Substituentgroup Y¹, selected from the following: a piperidinyl group, anazetidinyl group, a tetrahydropyranyl group, a morpholinyl group, or atetrahydropyridinyl group optionally substituted with 1-3 groupsindependently selected from Substituent group Y¹; Substituent group Y¹:a hydroxyl group, an amino group optionally substituted with 1-2 groupsindependently selected from Substituent group Y², a cyano group, afluorine atom, a methyl group, an ethyl group or an isopropyl groupoptionally substituted with 1-3 groups independently selected fromSubstituent group Y², a methoxy group optionally substituted with 1-3groups independently selected from Substituent group Y², an azetidinylgroup, a pyrrolidinyl group or a morpholinyl group optionallysubstituted with 1-3 groups independently selected from Substituentgroup Y², and any group optionally substituted with 1-3 groupsindependently selected from Substituent group Y², selected from thefollowing:

Substituent group Y²: a hydroxyl group, a fluorine atom, a methyl groupoptionally substituted with 1-3 groups independently selected fromSubstituent group Y³, a methoxy group optionally substituted with 1-3groups independently selected from Substituent group Y³, an amino groupoptionally substituted with 1-2 groups independently selected fromSubstituent group Y³, an azetidinyl group, a pyrrolidinyl group or amorpholinyl group optionally substituted with 1-3 groups independentlyselected from Substituent group Y³, and any group optionally substitutedwith 1-3 groups independently selected from Substituent group Y³,selected from the following:

Substituent group Y³: a hydroxyl group, a fluorine atom, a cyano group,a methyl group optionally substituted with 1-3 groups independentlyselected from Substituent group Y⁴, and a methoxy group optionallysubstituted with 1-3 groups independently selected from Substituentgroup Y⁴; Substituent group Y⁴: a fluorine atom.
 10. A compound selectedfrom the group consisting of:4-Fluoro-1-methyl-4-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine,4-{4-[(1R)-1-(Azetidin-1-yl)ethyl]phenyl}-1-[trans-4-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazole,(3R,6S)—N,N-Dimethyl-6-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}tetrahydro-2H-pyran-3-amine,4-Fluoro-1-methyl-4-{1-[(3R,6S)-6-(4-methyl-5-{[3-(propan-2-yl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)tetrahydro-2H-pyran-3-yl]-1H-1,2,3-triazol-4-yl}piperidine,3-{trans-4-[4-(4-Fluoro-1-methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl]cyclohexyl}-8-[3-(trifluoromethyl)phenoxy]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine,1,5-Anhydro-6-azetidin-1-yl-2,3,4,6-tetradeoxy-2-{4-[trans-4-(4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-1-yl}-D-erythro-hexitol,2-({5-[trans-4-(1-{trans-4-[3-(Fluoromethyl)azetidin-1-yl]cyclohexyl}-1H-1,2,3-triazol-4-yl)cyclohexyl]-4-methyl-4H-1,2,4-triazol-3-yl}methoxy)-4-(trifluoromethyl)pyridine,3-(trans-4-{1-[trans-4-(Azetidin-1-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4-methyl-5-{[3-(trifluoromethyl)phenoxy]methyl}-4H-1,2,4-triazole,4-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl)cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]morpholine,6-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-2-oxa-6-azaspiro[3.3]heptane,6-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-1-oxa-6-azaspiro[3.3]heptane,2-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-6-oxa-2-azaspiro[3.4]octane,{1-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]azetidine-3,3-diyl}dimethanol,Methyl3-{[4-methyl-5-(trans-4-{1-[trans-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methoxy}benzoate,8-Methyl-3-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene,and pharmacologically acceptable salts thereof.
 11. The compoundaccording to claim 1, wherein the compound is4-Fluoro-1-methyl-4-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}piperidine.12. The compound according to claim 1, wherein the compound is(3R,6S)—N,N-Dimethyl-6-{1-[trans-4-(4-methyl-5-{(1R)-1-[3-(propan-2-yl)phenoxy]ethyl}-4H-1,2,4-triazol-3-yl)cyclohexyl]-1H-1,2,3-triazol-4-yl}tetrahydro-2H-pyran-3-amine.13. The compound according to claim 1, wherein the compound is2-({5-[trans-4-(1-{trans-4-[3-(Fluoromethyl)azetidin-1-yl]cyclohexyl}-1H-1,2,3-triazol-4-yl)cyclohexyl]-4-methyl-4H-1,2,4-triazol-3-yl}methoxy)-4-(trifluoromethyl)pyridine.14. The compound according to claim 1, wherein the compound is6-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-2-oxa-6-azaspiro[3.3]heptane.15. The compound according to claim 1, wherein the compound is6-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-1-oxa-6-azaspiro[3.3]heptane.16. The compound according to claim 1, wherein the compound is2-[trans-4-(4-{trans-4-[4-Methyl-5-({[4-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-4H-1,2,4-triazol-3-yl]cyclohexyl}-1H-pyrazol-1-yl)cyclohexyl]-6-oxa-2-azaspiro[3.4]octane.17. The compound according to claim 1, wherein the compound is Methyl3-{[4-methyl-5-(trans-4-{1-[trans-4-(2-oxa-6-azaspiro[3.3]hept-6-yl)cyclohexyl]-1H-pyrazol-4-yl}cyclohexyl)-4H-1,2,4-triazol-3-yl]methoxy}benzoate.18. A method for increasing IL10 in a subject, comprising administeringan effective amount of a compound or a pharmacologically acceptable saltthereof according to claim 1 to a subject in need thereof.
 19. Apharmaceutical composition comprising a compound or a pharmacologicallyacceptable salt thereof according to claim 1 as an active ingredient.20. (canceled)
 21. A method according to claim 30, wherein theinflammatory disease is a peripheral inflammatory disease.
 22. A methodaccording to claim 30, wherein the inflammatory disease is a centralinflammatory disease.
 23. A method according to claim 21, wherein theperipheral inflammatory disease is a disease selected from the groupconsisting of rheumatoid arthritis, systemic lupus erythematosus,scleroderma, bronchial asthma, asthmatic bronchitis, diffuseinterstitial pneumonia, chronic obstructive pulmonary disease,ulcerative colitis, Crohn's disease, celiac disease, anal fistula,radiation enterocolitis, acute hepatitis, chronic hepatitis, fulminanthepatitis, autoimmune hepatitis, primary biliary cirrhosis, primarysclerosing cholangitis, alcoholic hepatitis, non-alcoholicsteatohepatitis, cirrhosis, peripheral neuritis, ankylosing spondylitis,eczema (acute, subacute, chronic), contact dermatitis, sunlight(ultraviolet light) dermatitis, radiation dermatitis, atopic dermatitis,seborrheic dermatitis, psoriasis vulgaris, arthropathic psoriasis,psoriatic erythroderma, pustular psoriasis, lichen planus, erythema,rosacea, urticaria, alopecia areata, pemphigus, erythroderma, acnevulgaris, pressure sore, wound, burn, conjunctivitis, keratitis,scleritis, acute/chronic otitis media, perennial allergic rhinitis, hayfever, sinusitis, laryngitis, esophagitis, refractory stomatitis,glossitis, acute/chronic salivary gland inflammation, angular cheilitis,cheilitis, Behcet's disease, multiple sclerosis, Type I diabetes, TypeII diabetes, atherosclerosis, pancreatitis and chronic heart failure.24. A method according to claim 21, wherein the peripheral inflammatorydisease is a disease selected from the group consisting of rheumatoidarthritis, systemic lupus erythematosus, bronchial asthma, ulcerativecolitis, Crohn's disease, celiac disease, anal fistula, radiationenterocolitis, acute hepatitis, autoimmune hepatitis, primary biliarycirrhosis, primary sclerosing cholangitis, alcoholic hepatitis,nonalcoholic steatohepatitis, ankylosing spondylitis, contactdermatitis, sunlight (ultraviolet light) dermatitis, atopic dermatitis,seborrheic dermatitis, psoriasis vulgaris, arthropathic psoriasis,psoriatic erythroderma, pustular psoriasis, lichen planus, erythema,rosacea, alopecia areata, pemphigus, erythroderma, acne vulgaris,pressure sore, wound, burn, sinusitis, laryngitis, esophagitis,refractory stomatitis, glossitis, acute/chronic salivary glandinflammation, angular cheilitis, cheilitis and Behcet's disease.
 25. Amethod according to claim 21, wherein the peripheral inflammatorydisease is a disease selected from the group consisting of rheumatoidarthritis, systemic lupus erythematosus, ulcerative colitis, Crohn'sdisease, celiac disease, anal fistula, radiation enterocolitis,autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis,ankylosing spondylitis, wound, refractory stomatitis, glossitis andBehcet's disease.
 26. A method according to claim 22, wherein thecentral inflammatory disease is a disease selected from the groupconsisting of Alzheimer's disease, Parkinson's disease, dementia withLewy bodies, multiple system atrophy, Pick's disease, progressivesupranuclear palsy, basal ganglia degeneration, frontotemporal lobardegeneration, Huntington's disease, amyotrophic lateral sclerosis,bulbar spinal muscular atrophy, spinal muscular atrophy, spinocerebellardegeneration, multiple sclerosis, Creutzfeldt-Jakob disease, lethalfamilial insomnia, Gerstmann-Streisler-Shinker syndrome, Down syndrome,Niemann-Pick disease, cerebral amyloid angiopathy, HIV encephalopathy,influenza encephalopathy, hepatic encephalopathy, progressive multifocalleukoencephalopathy, anti-NMDA receptor antibody encephalitis,cerebrovascular disorder, traumatic brain injury, spinal cord injury,hypoxia encephalopathy, epilepsy, optic neuritis, congenital metabolicbrain disease, Wernicke encephalopathy, autism spectrum disorder,attention deficit/hyperactivity disorder, tic disorder, schizophrenia,bipolar disorder, major depressive disorder (treatment-resistantdepression, postpartum depression), persistent depressive disorder(dysthymia), menstruation pre-discomfort mood disorder, anxietydisorder, localized phobia, panic disorder, obsessive compulsivedisorder, trauma and stress factor related disorder, eating disorder,circadian rhythm sleep/wake disorder, narcolepsy, substance-relateddisorder (alcohol dependence, drug dependence), impulse controldisorder, delirium, personality disorder, and Rett syndrome.
 27. Amethod according to claim 22, wherein the central inflammatory diseaseis a disease selected from the group consisting of Alzheimer's disease,Parkinson's disease, dementia with Lewy bodies, multiple system atrophy,Pick's disease, progressive supranuclear palsy, basal gangliadegeneration, frontotemporal lobar degeneration, Huntington's disease,amyotrophic lateral sclerosis, bulbar spinal muscular atrophy, spinalmuscular atrophy, spinocerebellar degeneration, multiple sclerosis,Creutzfeldt-Jakob disease, schizophrenia, bipolar disorder, majordepressive disorder (treatment-resistant depression, postpartumdepression), persistent depressive disorder (dysthymia), menstruationpre-discomfort mood disorder, anxiety disorder, localized phobia, panicdisorder, obsessive compulsive disorder, trauma and stress factorrelated disorder, eating disorder, circadian rhythm sleep/wake disorder,narcolepsy, substance-related disorder (alcohol dependence, drugdependence), impulse control disorder, delirium, personality disorder,and Rett syndrome.
 28. A method according to claim 22, wherein thecentral inflammatory disease is a disease selected from the groupconsisting of schizophrenia, bipolar disorder, major depressive disorder(treatment-resistant depression, postpartum depression), persistentdepressive disorder (dysthymia), menstruation pre-discomfort mooddisorder, anxiety disorder, localized phobia, panic disorder, andobsessive compulsive disorder.
 29. (canceled)
 30. A method of preventingand/or treating an inflammatory disease in a subject, comprisingadministering to an effective amount of a pharmaceutical compositionaccording to claim 19 to a subject in need thereof.
 31. A crystal of acompound according to claim 11, having peaks at diffraction angles(2θ(°)) of about 3.9, 4.1, 8.34, 12.6, 16.2, 18.4, 19.5 and 22.3 bypowder X-ray diffraction.
 32. (canceled)
 33. A crystal of a compoundaccording to claim 12, having peaks at diffraction angles (2θ(°)) ofabout 3.8, 16.4, 18.0, 18.6, 19.8, 21.2 and 22.7 by powder X-raydiffraction.
 34. (canceled)
 35. A crystal of a compound according toclaim 13, having peaks at diffraction angles (2θ(°)) of about 13.5,15.7, 17.2, 17.8, 18.2, 19.2, 20.4, 20.8, 22.0 and 27.2 by powder X-raydiffraction.
 36. (canceled)
 37. A crystal of a compound according toclaim 14, having peaks at diffraction angles (2θ(°)) of about 3.3, 13.4,15.5, 16.8, 17.5, 17.9, 18.9, 20.4, 21.8 and 26.9 by powder X-raydiffraction.
 38. (canceled)
 39. A crystal of a compound according toclaim 15, having peaks at diffraction angles (2θ(°)) of about 13.2,15.8, 16.5, 17.8, 18.1, 20.3, 20.8, 21.4 and 27.9 by powder X-raydiffraction.
 40. (canceled)
 41. A crystal of a compound according toclaim 16, having peaks at diffraction angles (2θ(°)) of about 14.2,16.8, 17.4, 18.2, 18.6, 19.5, 20.0, 20.9, 21.6 and 21.8 by powder X-raydiffraction.
 42. (canceled)
 43. A crystal of a compound according toclaim 17, having peaks at diffraction angles (2θ(°)) of about 15.4,17.6, 17.9, 18.4, 18.7, 19.2, 20.2, 20.7, 23.0 and 23.8 by powder X-raydiffraction.
 44. (canceled)